Effects of Dietary Intervention On Human Diseases

Signal Transduction and Targeted Therapy www.nature.
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REVIEW ARTICLE OPEN
Effects of dietary intervention on human diseases: molecular

mechanisms and therapeutic potential
Yu-Ling Xiao 1,2
, Yue Gong1,2, Ying-Jia Qi , Zhi-Ming Shao1,2 and Yi-Zhou Jiang1,2 ✉
1,2
Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary
interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative
diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated
substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a
hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune
regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence
tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby
increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of
cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies
remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the
potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein
1234567890();,:
restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the
multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and
underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions
as adjunctive therapies in disease management.
Signal Transduction and Targeted Therapy (2024)9:59 ; https://doi.org/10.1038/s41392-024-01771-x
INTRODUCTION adherence to the plant-based Paleolithic diet and a Paleolithic-like

Nutrients play a crucial role in regulating various physiological lifestyle has been found to significantly reduce the risk of
processes.1 The main source of nutrients is usually considered to colorectal cancer (CRC), especially in individuals with a body mass
be diet. The quantity, quality, and composition of the food index (BMI) less than 30.11 Although many cancer patients are
consumed, as well as the timing of meals, directly impact human interested in using dietary intervention to improve cancer therapy
health by influencing the availability of nutrients.2 Although there outcomes or even using it as a key component of the therapeutic
have been advancements in understanding the link between diet process,12 there is currently no solid evidence showing that any
and disease in recent years, there is still much to learn about how nutrition-related regimen can be a primary treatment for cancer.13
specific dietary components affect disease risk and prevention.3 However, preclinical studies suggest that calorie and energy
Epidemiological studies have linked various dietary patterns to restrictions can hinder tumor growth and progression and
cancer and other diseases.4 For instance, diets high in saturated increase the efficacy of chemotherapy and radiotherapy.14,15 A
fats and sugars have been associated with an increased risk of rising number of clinical trials are exploring the impact of dietary
cardiovascular diseases (CVD) and type 2 diabetes.5 Conversely, interventions or nutritional supplements in conjunction with
diets rich in fiber, fruits, and vegetables are associated with a standard antitumor therapies, with some showing clinical
lower risk of these conditions.6 Similarly, conditions such as benefits.16,17
osteoporosis and certain neurological disorders have also shown Diet is a crucial source of nutrients for tumors and has emerged
links to dietary patterns, highlighting the broad influence of diet as a key component in determining whole-body metabolism.18
on overall health.7,8 In the context of cancer, increased consump- The nutrients in the tumor microenvironment (TME) largely
tion of alcohol and red or processed meat is associated with a regulate tumor cell and immune cell metabolism.19 Recent
heightened risk of cancer, whereas adherence to a Mediterranean evidence suggests that metabolic reprogramming, a crucial
dietary pattern—characterized by high intake of fruits, vegetables, hallmark of cancer, involves several metabolic adaptations by
whole grains, legumes, fish, and olive oil, along with moderate tumor cells to sustain proliferation and metastasis in the TME.19–21
consumption of dairy products such as yogurt—may confer The TME constitutes a multifaceted and dynamic ecosystem
protective effects against carcinogenesis.9,10 Similarly, a strong comprising an assortment of cell types, including tumor cells,
1
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China and 2Department of Oncology, Shanghai
Medical College, Fudan University, Shanghai 200032, China
Correspondence: Yi-Zhou Jiang (yizhoujiang@fudan.edu.cn)
These authors contributed equally: Yu-Ling Xiao, Yue Gong, Ying-Jia Qi
Received: 1 August 2023 Revised: 5 February 2024 Accepted: 18 February 2024
© The Author(s) 2024

Effects of dietary intervention on human diseases: molecular mechanisms. . .
Xiao et al.
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Dietary Intervention
• Calorie restriction
Metabolic Reprogramming • Fasting or fasting-mimicking diet
• Ketogenic diet
• Glucose metabolism • Protein restriction diet
• Lipid metabolism • High-salt diet
• Amino acid metabolism • Obesity and high-fat diet
Diseases
• Cancer
TME • Neurodegenerative diseases
• Autoimmune diseases
• Cardiovascular diseases
• Metabolic disorders
Gut Microbiome
Therapy
Fig. 1 Overview of the relationship between dietary interventions and diseases. The cellular microenvironment, including the tumor
microenvironment (TME), plays a crucial role in disease biology, and diet serves as a vital source of nutrients that can influence these
microenvironments. Metabolic reprogramming, a prominent feature associated with disease progression, can affect cell metabolism and
immune function. Dietary interventions, such as caloric restriction (CR), fasting-mimicking diet (FMD), and ketogenic diet (KD), can modulate
the progression and treatment sensitivity of various diseases, including cancer. Additionally, dietary interventions can alter the composition
and functional capacity of the gut microbiome, thereby indirectly influencing the progression and treatment of diseases. These direct and
indirect effects of dietary interventions can influence metabolic reprogramming, modulate immune responses, and potentially enhance the
clinical efficacy of treatments for various diseases. This figure was created with BioRender.com
immune cells, and stromal cells, in addition to components of the As our understanding of the complex relationships between
extracellular matrix. The interplay among these constituents, along diet, metabolic reprogramming, and various diseases continues to
with the challenging environmental conditions, exerts a significant evolve, it becomes increasingly evident that dietary components
influence on the growth trajectory and progression of tumors.22 and patterns significantly influence disease risk, prevention, and
For example, oxygen levels within the TME can vary due to progression. This review delves into the unique metabolic
increased metabolic demand from rapidly proliferating tumor characteristics and nutrient availability of tumors. Furthermore,
cells, resulting in low oxygen tension, known as hypoxia, in tissues. we investigate recent evidence and emerging trends concerning
In addition, nutrient availability, including the availability of the effects of dietary interventions on both cancer and other
glucose, fatty acids, and amino acids, can vary within the TME, diseases, underscoring the potential therapeutic benefits these
impacting metabolic processes and energy production. The dietary strategies may offer to a wide range of patients (Fig. 1).
accumulation of metabolic waste products and alterations in pH
can further contribute to a hostile TME, which can impair immune
function and promote tumor progression.23 These factors, along METABOLIC CHARACTERISTICS AND NUTRIENT AVAILABILITY
with dynamic interactions within the TME, play crucial roles in IN THE TUMOR
influencing tumor proliferation and the effectiveness of antitumor Cellular metabolism encompasses a complex array of biochemical
immune responses.24 reactions that utilize specific nutrients, including carbohydrates,
Signal Transduction and Targeted Therapy (2024)9:59

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M1-like macrophages
Naïve T cells M2-like macrophages
Glycolysis and PPP

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Fig. 2 Major metabolic pathways associated with different immune cell subtypes within the tumor microenvironment (TME). Summary of the
main metabolic pathways of immune cells, highlighting the distinctive metabolic characteristics and requirements of different subsets of
immune cells. This figure was created with BioRender.com
fatty acids, and amino acids. These nutrients are the primary glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphor-
sources for maintaining energy homeostasis and synthesizing ylation (OXPHOS), the pentose phosphate pathway (PPP), fatty
macromolecules.25 Our focus here is on cancer metabolism, which acid oxidation (FAO), fatty acid synthesis (FAS) and the amino acid
differs from that in corresponding healthy tissues in terms of metabolic pathway30 (Fig. 2).
nutrient levels and metabolic demands.26 Within the TME, cancer
cells can establish an immunosuppressive metabolic microenvir- Glucose metabolism
onment by depriving immune cells of vital metabolites such as Glucose serves as a vital energy source, facilitating the functioning
glucose and oxygen while also elevating the levels of mediators of immune cells. Once transported across the plasma membrane,
such as lactate and adenosine that limit the function of immune glucose is metabolically processed via three distinct pathways:
cells.27 Therefore, different subsets of immune cells undergo glycolysis, the PPP, and the TCA cycle. Glycolysis, which occurs in
metabolic reprogramming in tumors, and specific nutrients are the cytosol, transforms glucose into pyruvate and lactate,
required for these metabolic programs.28,29 Generally, the meta- simultaneously generating adenosine triphosphate (ATP). Under
bolic programs that play vital roles in immune cells include aerobic conditions, pyruvate is channeled into the TCA cycle,

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where OXPHOS occurs, yielding additional ATP. Moreover, energy production to sustain their function, including cytokine
glucose-6-phosphate, a derivative of glycolysis, fuels the PPP, production, antigen processing and presentation, and the
culminating in the production of ribose-5-phosphate and nicoti- stimulation of T cells.48 Furthermore, different subsets of macro-
namide adenine dinucleotide phosphate (NADPH). Recent phages present distinct metabolic functions. M1-like macrophages
research has indicated a marked disparity in energy consumption predominantly utilize anabolic metabolism, specifically glycolysis
between immune cells in resting and activated states.18 Although and the PPP, to generate energy and synthesize cellular
glycolysis does not generate as many ATP molecules as OXPHOS, components, whereas M2-like macrophages are more reliant on
glycolysis produces ATP more rapidly, which is important to OXPHOS, particularly through the enhancement of FAO.49
metabolically active immune cells.
Cancer cells are characterized by their rapid proliferation, Lipid metabolism
primarily fueled by the consumption of glucose as an energy Lipids, such as fatty acids, triglycerides, cholesterol, phospholipids,
source. Intriguingly, these cells continue to rely on glycolysis for and sphingolipids, play crucial roles as precursors to many
energy production even in the presence of ample oxygen, a important biological molecules.50 Lipids, including substances
phenomenon referred to as the “Warburg effect”.31 This unique such as cholesterol and fatty acids that are widely distributed in
phenomenon leads to glucose depletion and lactic acid (LA) organelles, are key components of internal cellular membranes.
accumulation in the microenvironment, ultimately inhibiting Moreover, lipids are essential biological molecules that provide
antitumor responses.32 High glycolytic rates in triple-negative energy during nutrient deficiency, participate in the synthesis of
breast cancer cells promote the infiltration of myeloid-derived complex fat-containing substances, and aid in cellular signal
suppressor cells (MDSCs) and suppress T-cell function, while transmission as second messengers.51 Lipids within the micro-
suppressing glycolysis inhibits tumor colony-stimulating factor environment profoundly influence the proliferation of cancer cells
(CSF) expression and MDSC development.33 Cancer cells produce and regulate the functional activity of immune cells.
LA through glycolysis, which reduces the antitumor activity of Cancer cells undergo metabolic reprogramming of lipids in the
CD8+ T cells and natural killer (NK) cells. However, the activation of tumor niche. The activation of adipocytes triggers the lipolysis of
LA metabolism pathways in regulatory T cells (Tregs) is increased, stored triglycerides and secretion of fatty acids. Cancer cells can
and these cells adapt to high-LA conditions.34,35 Furthermore, then take up these fatty acids to fulfill their lipid requirements for
cancer cells can take advantage of immune cells by utilizing their rapid growth.52 Research has also demonstrated that ovarian
metabolic byproducts. LA can shift tumor-associated macro- cancer cells stimulate membrane cholesterol efflux from TAMs,
phages (TAMs) from a proinflammatory (M1-like) to an anti- fostering an environment that promotes tumor growth by
inflammatory (M2-like) phenotype in the TME. Notably, lactate- enhancing interleukin (IL)-4-mediated reprogramming and sup-
activated TAMs enhance cancer cell adhesion, migration, invasion pressing IFNγ-induced gene expression. The deletion of ABC
in vitro, and promote metastasis in vivo.36 transporters, responsible for cholesterol efflux, reversed the
T cells play crucial roles in the TME. Upon activation, these cells tumor-promoting functions of TAMs, leading to reduced tumor
undergo metabolic reprogramming, which subsequently yields progression.53
diverse functional outcomes. Naïve T cells, which are metabolically Furthermore, elevated cholesterol levels in the microenviron-
quiescent, exhibit basic nutrient intake rates and low glycolysis ment stimulate the expression of immune checkpoints, including
rates. They primarily generate ATP through TCA cycle-fueled PD-1, 2B4, TIM-3, and LAG-3, in T cells, driving T-cell exhaustion via
OXPHOS.37 The activation of specific membrane receptors triggers the activation of the endoplasmic reticulum stress response.54 In
the differentiation of naïve T cells into effector T cells, also known contrast to the negative effects of reprogramming T-cell lipid
as Teff cells. This process is accompanied by a pronounced increase metabolism on antitumor immunity, the inhibition of ACAT1, a
in both energy demand and biosynthetic activity within Teff cells. pivotal enzyme responsible for cholesterol esterification in CD8+
In Teff cells, the metabolic state is changed to increasingly rely on T cells, results in elevated cholesterol levels in the plasma
glycolysis, as these cells upregulate GLUT1, increase glucose membrane. This increase subsequently amplifies TCR signaling
intake.38–41 Simultaneously, this metabolic alteration benefits Teff and promotes antitumor activity. These findings highlight the
cells by reducing their reliance on oxygen for energy production, complex mechanisms through which cholesterol regulates T-cell
which enables them to maintain cytokine production and cytolytic function.55
activity even when they migrate into microenvironments within For efficient tumor antigen processing and presentation to
solid tumors that have low oxygen levels.42 In contrast to naïve T cells, activated DCs need high rates of cell surface or secretory
and Teff cells, memory T cells undergo a metabolic rewiring protein biosynthesis, which is partly regulated by FAS-induced
process that leads them to enter a quiescent state characterized increases in cytokine production.56 Teff cells depend mainly on FAS
by elevated OXPHOS rates compared to the glycolysis rate.43 to support inflammatory cytokine secretion and proliferation,
Tregs, known for their suppressive function, exhibit decreased while naïve T cells and memory T cells maintain their basic
glycolysis rates and primarily rely on OXPHOS to support their functions by increasing the FAO rate.57–59 Although Teff cells rely
function, while glycolysis is crucial for their migration.44 It has mainly on glycolysis for energy, CD8+ T cells that undergo
been reported that the Treg-specific transcription factor FOXP3 enhanced FAO exhibit stable antitumor functions even under
reprograms Treg metabolism by suppressing Myc expression and conditions of low glucose and oxygen levels. By promoting fatty
glycolysis while promoting OXPHOS and NAD(H) oxidation. This acid catabolism, CD8+ T cells exhibit increased functionality, and
adaptation enables Tregs to be more adaptable to low-glucose the efficacy of immunotherapy in patients with melanoma can
and/or lactate-rich microenvironments.45 thus increase.60
There are several other types of cells within the TME that exhibit While these studies indicate a positive influence of lipids on the
distinct metabolic functions. In the case of NK cells, glycolysis and functionality and metabolism of CD8+ T cells in the TME, it is
OXPHOS play important roles in maintaining their cytotoxicity, as important to note that alterations to T-cell lipid metabolism might
indicated by the inhibition of these processes leading to attenuate their antitumoral effects. In obesity-related breast
diminished expression of IFNγ and Fas ligands.46 Researchers cancer murine models, the activation of STAT3 triggered an
have shown that transcription factor-controlled glucose metabo- increase in FAO in CD8+ T cells, which suppressed glycolysis and
lism, specifically by sterol regulatory element-binding proteins weakened their tumor-suppressing ability.61 Moreover, enhanced
(SREBPs), which conventionally control lipid synthesis, is essential lipid uptake and peroxidation can result in high oxidative stress,
for metabolic reprogramming in activated NK cells.47 Dendritic which leads to CD8+ T cell dysfunction. CD36, a fatty acid
cells (DCs), on the other hand, rely on glycolysis and the PPP for scavenger receptor, facilitates the incorporation of arachidonic

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acid into CD8+ T cells. This process subsequently triggers lipid augments the efficacy of antitumor immune responses. The
peroxidation and ferroptosis, events that cumulatively attenuate compound V-9302, an inhibitor of the glutamine transporter,
the antitumor immune response and reduce the efficacy of selectively impedes glutamine uptake in cancer cells while
immunotherapy.62–64 simultaneously enhancing both glutamine assimilation and
Lipid metabolism also plays an active role in regulating Treg glutathione synthesis in Teff cells, ultimately enhancing their
function. Fatty acid synthase (FASN)-mediated FAS contributes to function.80
the proliferation and maturation of Tregs, and FAO provides the Tryptophan is another essential amino acid. Following its entry
energy crucial for Treg infiltration into the TME.65 Research has into eukaryotic cells via the transport proteins SLC1A5 or SLC7A5,
shown that OX40 plays a role in modifying the lipid composition tryptophan is primarily subjected to three primary metabolic
of Tregs, leading to the proliferation of OX40+ Tregs in the TME. pathways: incorporation into protein synthesis, metabolism via the
This effect is achieved through increased FAS expression and kynurenine (Kyn) pathway, or conversion through the serotonin
glycolysis rate in Tregs.66 CD36, via the peroxisome proliferator- pathway.81 Notably, a substantial fraction of tryptophan is directed
activated receptor-β (PPAR) signaling pathway, maintains the through the Kyn pathway, culminating in the production of a suite
mitochondrial fitness of Tregs, promoting Treg viability and of metabolites with significant physiological implications.82
inhibitory functions.67 SREBPs have been found to show increased Tryptophan plays a crucial role in determining the strength and
activity in Tregs that infiltrate tumors. Inhibiting FAS and effectiveness of the T cell response by affecting its availability in
metabolic signaling by targeting SREBPs has been shown to the microenvironment.83 However, within the tumor niche, cancer
effectively activate the antitumor immune response without cells, MDSCs, TAMs, suppressive DCs, and cancer-associated
causing autoimmune toxicity. When the SREBP-SCAP axis was fibroblasts, among other cell types, exhibit upregulated expression
inhibited, in addition to tumor growth attenuation, immunother- of indoleamine 2,3-dioxygenase (IDO), which metabolizes trypto-
apy effectiveness was boosted. These findings suggest that phan into suppressive kynurenine to promote Tregs and suppress
SREBPs may be promising targets for cancer therapy.68 CD8+ T cell function.84–86 Most cancer cells overexpress IDO, and
High expression of FASN in TAMs promotes the accumulation of the level of kynurenine in the microenvironment is associated with
fatty acids, leading to enhanced tumor immune tolerance via the poor prognosis in multiple solid and hematological malignan-
FAO pathway.69 Notably, lipid metabolism differs between M1-like cies.87 Kynurenine has been found to bind to the aryl hydrocarbon
and M2-like macrophages. M1-like macrophages prevalently receptor (AHR) in naïve CD4+ T cells, which promotes Treg
engage the FAS pathway, while M2-like macrophages predomi- differentiation.87
nantly utilize the mitochondrial FAO pathway for their bioener- An additional metabolite generated through the Kyn pathway is
getic demands.70,71 Receptor-interacting protein kinase 3 (RIPK3), the essential redox cofactor nicotinamide adenine dinucleotide (NAD
which is crucial for necroptosis, is found to be diminished in +), a molecule of fundamental importance for the maintenance of
hepatocellular carcinoma (HCC)-associated macrophages, leading cellular homeostasis.88 In particular, cancer cells heavily depend on
to inhibited caspase1-mediated cleavage of PPAR, a process vital NAD+ to promote metabolic reprogramming and meet higher
for enhancing fatty acid metabolism, including FAO. This demands for ATP. Elevated NAD+ levels have been demonstrated to
metabolic shift results in increased accumulation and polarization promote the proliferation of cancer cells.89 Although the majority of
of M2-like macrophages in the TME, contributing to accelerated studies suggest that an increase in NAD+ drives cellular proliferation,
HCC growth.72 prior investigations have proposed that a decrease in NAD+ levels
MDSCs also exert a substantial influence in suppressing can lead to genomic instability, subsequently instigating liver
antitumor immunity in the microenvironment, and they can be tumorigenesis.90 Moreover, tryptophan metabolism mediated by
categorized into monocytic MDSCs (M-MDSCs) and granulocytic IDO affects not only the Kyn pathway but also other pathways,
MDSCs (PMN-MDSCs).73 Tumor-infiltrating MDSCs increase fatty such as the purine, nicotinamide, and pyrimidine metabolism
acid uptake and induce FAO.74 The accumulation of lipids in pathways, ultimately leading to decreased T-cell function.91 In
MDSCs increases oxidative metabolism, resulting in MDSC addition to IDO, another enzyme, tryptophan 2,3-dioxygenase
acquisition of an immunosuppressive and anti-inflammatory (TDO), is involved in tryptophan catabolism. High TDO expression
phenotype.75 has been shown to impair T-cell antitumor immunity and to be
correlated with poor clinical prognosis. Suppressing TDO
Amino acid metabolism expression can increase the antitumor efficacy of immune
Amino acids are the primary substrates for protein biosynthesis, checkpoint inhibitors (ICIs).92
and recent evidence emphasizes the critical role of amino acid In addition to the aforementioned amino acids, other amino
availability and metabolism in the regulation of antitumor acids play crucial roles in regulating tumor metabolism. T-cell
immunity. proliferation relies heavily on arginine consumption. L-arginine
Glutamine is the most abundant amino acid and a crucial supplementation has been shown to facilitate the metabolic shift
energy substrate, as well as an important nitrogen and carbon from glycolysis to OXPHOS, enhancing T-cell survival and boosting
donor for various biosynthetic precursors.76 Teff cells require antitumor responses of CD8+ tumor infiltrating lymphocytes
higher levels of glutamine than naïve T cells due to their rapid (TILs).93 Notably, the functional differences resulting from TAM
proliferation and demand for sufficient raw materials for macro- polarization partially depend on arginine metabolism. In macro-
molecule synthesis and cytokine secretion.77 Cancer cells have phages with the M1-like phenotype, arginine is converted into
been shown to exhibit the highest glutamine uptake capacity and nitric oxide (NO) and citrulline via inducible nitric oxide synthase
consume most of the glutamine in the microenvironment.76 In (iNOS), and this anabolic pathway is closely associated with
turn, elevated glutamine consumption by cancer cells diminishes macrophage cytotoxicity and antitumor effects. Conversely, in
the glutamine supply necessary for T cells, consequently impeding macrophages with the M2-like phenotype, arginine is hydrolyzed
the antitumor immune response.78 In the microenvironment, to yield ornithine and urea through arginase 1 (Arg1).94 This
cancer cells consume glutamine to synthesize γ-aminobutyric acid metabolic shift affects arginine availability, which in turn impacts
(GABA) via glutamate decarboxylase 1 (GAD1). By activating the the activation and proliferation of T cells and NK cells, leading to
GABAB receptor, GABA inhibits GSK-3β activity, which enhances immune suppression within the microenvironment. Notably, Arg1
β-catenin signaling, promoting cancer cell proliferation while expression in MDSCs contributes to arginine depletion in the
suppressing intratumoral infiltration of CD8+ T cells.79 Further- microenvironment, further inhibiting T-cell antitumor function and
more, elimination of glutaminase, a vital enzyme for glutamine reducing their survival.95,96 In addition, depletion of cystine and
metabolism, within tumor cells stimulates T-cell activation and cysteine is also linked to the immunosuppressive effect of MDSCs.

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T cells are unable to synthesize the essential amino acid cysteine diet. Moreover, high-salt diet (HSD), although not directly
from substances such as cystine or methionine, necessitating its involving macronutrients, is noteworthy due to its potential
import from external sources for their functionality.97 MDSCs impact on tumor biology. Therefore, an in-depth discussion on the
import cystine but do not release cysteine, thus the levels of role of HSD in cancer research and treatment is included in our
cysteine in the microenvironment are regulated, inhibiting T-cell exploration.
activation.98 Asparagine is another amino acid that significantly The connections between various dietary patterns and cancer risk
boosts CD8+ T-cell activation and antitumor responses. Restricting are likely rooted in several biological mechanisms, such as
dietary asparagine or inhibiting its uptake impaired T-cell inflammation and immune function; specific factors, such as the
activation and differentiation into memory-like cells.99 Cancer gut microbiota and their metabolites; unfavorable events, such as
cells consume higher levels of methionine due to increased certain epigenetic changes and metabolic or hormonal disruptions;
expression of its transporter (SLC43A2), which inhibits methionine and stress, such as oxidative stress.108 Alterations in dietary
metabolism and function in CD8+ T cells by altering histone composition impact not only the availability of nutrients within
methylation patterns.100 tumor cells but also the surrounding microenvironment, thereby
offering potential opportunities to impede tumor growth109 (Table 1).
Organ-specific metabolic profiles
Understanding the metabolic differences between various organs Calorie restriction
is critical for developing targeted therapeutic strategies in cancer Effective CR is a dietary intervention that reduces energy intake by
treatment. Each organ has unique metabolic demands and approximately 15–30% while maintaining a balanced proportion
pathways that can be dysregulated in cancer, leading to distinct of macronutrients and preventing malnutrition.110 CR has been
metabolic profiles for different types of tumors.101 This organ- shown to prolong life and reduce age-related diseases, including
specific metabolic reprogramming plays a key role in cancer cancer, in experimental models.111
progression and survival, and its understanding could be Although the antitumor effect of CR has been confirmed, the
leveraged for therapeutic benefits. underlying mechanism remains unclear. Nonetheless, it is believed
Consider primary brain tumors as an example. These tumors, that the tumor-inhibiting effect is partially mediated by several
often found nestled within the intricate neural networks of the biological changes, such as increased apoptosis rates in cancer
brain, exhibit a remarkable metabolic flexibility.102 They are known cells, decreased circulating blood glucose levels, inhibited insulin-
to express elevated levels or alternative isoforms of glycolytic like growth factor 1 (IGF-1) signaling, reduced insulin levels, and
enzymes, a trait that points towards a potential therapeutic mediators that regulate metabolic pathway activation and inhibit
opportunity.103 Specifically, the therapeutic strategy of glucose angiogenesis.112 In particular, controlling IGF-1 signal transduction
deprivation could selectively starve brain tumor cells while sparing is a critical component underlying the antitumor effects of CR. The
healthy neurons, which are capable of surviving on alternative IGF-1 signaling pathway is frequently activated in cancer cells, and
fuels such as ketone bodies.104 Similarly, HCC cells undergo a it shifts metabolic resources toward growth and proliferation.
significant metabolic shift from glucose production (a state known Therefore, the reduction in IGF-1 levels in response to CR leads to
as gluconeogenesis) to glucose usage.105 HCC cells also exhibit a attenuated tumor growth and progression.113 The impact of CR on
marked increase in amino acid metabolism, particularly in the cancer is also interconnected with mutations and oncogenic
metabolism of glutamine.106 Additionally, studies have shown that pathways. A study showed that CR results in a reduction of insulin
HCC cells often exhibit abnormal lipid accumulation, increased levels, thereby diminishing tumor PI3K signaling.114 CR has also
FAS, and enhanced cholesterol metabolism. These changes been found to suppress xenograft tumor growth by upregulating
contribute to the aggressive and metastatic behaviors of HCC.107 the aldolase A (ALDOA)/DNA-PK/p53 pathway, with ALDOA acting
Moreover, hormone-sensitive tissues such as the breast, as a potential oncogene that can also activate the tumor
endometrium, and prostate also exhibit significant metabolic suppressor p53.115 Moreover, CR has been shown to modify the
fluctuations in response to hormone levels.101 Hyperactivation of cancer stem cell (CSC) phenotype, reducing their carcinogenic and
the PI3K pathway, a lipid kinase that promotes proliferation and metastatic potential. Notably, in MMTV-ErbB2 transgenic mice, the
nutrient uptake in response to growth signals, has been CSC subpopulation was most affected by CR, as shown by a
implicated in breast and endometrial cancers, providing a possible reduction of luminal cells (CD24high/CD49flow), putative mammary
mechanism for hormonal therapy evasion.107 This pathway could reconstituting unit subpopulations (CD24high/CD49fhigh) and
be a potential target for therapeutic interventions, particularly in luminal progenitor cells (CD61high/CD49fhigh). These effects were
hormone therapy-resistant cancers. largely attributed to the concurrent inhibition of estrogen receptor
In summary, understanding organ-specific metabolic profiles and ErbB2 signaling.116
and their dysregulation in cancer can open up new avenues for CR has been shown to shape the TME in several ways,
targeted cancer therapy. By exploiting these unique metabolic including through the specific reduction in the number of TAMs,
dependencies of tumors, more effective and personalized treat- increase in the formation of CD8+ cytotoxic T cells and memory
ment strategies can be developed. T cells, and negative modulation of immunosuppressive Treg
cell activity and immunosuppressive cytokine levels.117 Addi-
tionally, CR promotes favorable changes in the immune
TARGETED DIETARY INTERVENTIONS AND MECHANISTIC signature, providing enhanced protection against tumor growth
INSIGHTS INTO THEIR IMPACT ON CANCER and metastasis, possibly in part by remodeling the TME. In mice,
Understanding the metabolic pathways of glucose, lipids, and no impact of a CR diet was observed on the number of CD4+ or
amino acids lays a crucial foundation for exploring the effects of CD8+ cells in the TME; however, the cytotoxic killing potential of
various dietary restrictions. Macronutrients, including carbohy- these cells was elevated. Notably, higher expression of CD103+,
drates, fats, and proteins, are the primary sources of energy for our a marker of crucial tissue-resident memory T cells that possess
bodies, and they each follow distinct metabolic pathways. By enhanced cytotoxic capacity and can contribute to tissue
manipulating the relative intake of these macronutrients, we can protection against tumor cell invasion, was found. Additionally,
influence the metabolic pathways they utilize and thereby exert a downward trend in the frequency of Tregs was observed, and
control over our systemic metabolism. This concept forms the a significant reduction in the total number of MDSCs was
basis for various dietary restrictions and special diets, such as detected.118 Hence, it was concluded that CR not only inhibits
caloric restriction (CR), fasting or fasting-mimicking diet (FMD), cancer cell proliferation but also helps maintain antitumor
ketogenic diet (KD), high-fat diet (HFD), or amino acid-defined immunity.

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Table 1. Preclinical studies supporting dietary interventions in cancer
Dietary intervention Cancer type Results References
Calorie restriction Breast cancer Ly6C+-expressing memory T cells (CD4+Ly6C+)↑, Ly6C+CD8+ cells↑, 118
CD103+CD4+ cells↑, CD103+CD8+ cells↑

FOXP3+CD8+ Tregs↓, MDSCs↓, PMN-MDSC↓, TAMs↓
124
(1) ER (energy restriction) vs. AL: the expression of Aicda, Pdcd1, Ifng,
Foxp3, and Ido1↓
(2) PA (physical activity) + ER vs. SED (sedentary)+ AL:
(i) For tumors at equal size: CD8+ T cells↑, CD4+ T cells↑, CD8/total
MDSC ratio↑, MSDCs↓, M-MSDCs↓
(ii) For tumors at day 35 post-tumor implantation: CD8+ T cells↑,
CD8/total MDSC ratio↑, MSDCs↓, M-MSDCs↓, PMN-MSDCs↓
Colorectal cancer CD8+ T cells↑, IFNγ+CD8+ T cells↑ 290
+ + 236
Fasting-mimicking diet Breast cancer CTLA-4 Tregs↑, PD-1 Tregs↑
Myeloid cells↓, M2-like macrophages↓, PMN-MDSCs↓, M-MDSCs↓, PD-
L1+ PMN-MDSCs↓, PD-L1+ M-MDSCs↓
137
Alternate day fasting Colorectal cancer TAMs↓, M2-like macrophages↓
151
Ketogenic diet Colorectal cancer Macrophages↑, M2 to M1 TAM polarization↑
Lactate↓
147
Hopx activation↑, colonic crypt cell proliferation↓, tumor growth↓
148
Non-small cell lung cancer Per↑, AMPK activation↑, SIRT1↑, tumor cell apoptosis↑, tumor cell
growth↓
149
Neuroendocrine cancer PI3K-Akt-mTOR signaling↓, tumor growth↓
+ + + + 152
Glioma CD4 T cells↑, CD4 T cells/Tregs ratio↑, IFNγ CD8 T cells↑,
TNF+CD8+ T cells↑, IL-2+CD8+ T cells↑, cytotoxic capability of CD8+
T cells↑, IFNγ+ NK cells↑, TNF+ NK cells↑
PD-1+CD8+ T cells↓, CTLA-4+CD8+ T cells↓, IL-10+ Tregs↓
156
Colorectal cancer Tumor cell ferroptosis↑, cachexia onset↑, overall survival↓
Adrenocortical cancer
163
Dietary restriction of Prostate cancer M1-like macrophages↑, M1-like macrophages linked proteins
protein/80% methionine- (CXCL11/I-TAC, IL-1α, IL-1β, IL-12p40, M-CSF, and IL-17A) ↑, CD8+ T
restricted diet cells↑, granzyme B+CD8+ T cells↑
M2-like macrophages↓, PMN-MDSCs↓, M-MDSCs↓, M2-like
macrophages linked proteins (C-reactive protein, FGF acidic, IL-33,
leptin, and MMP9) ↓
Dietary methionine Colorectal cancer CD8+ T cells↑, GZMB+CD8+ T cells↑, IFNγ+CD8+ T cells↑ 162
restriction L-cystathionine (LCYH)↓, SAM↓, 5’-methylthioadenosine (MTA)↓,

S-adenosylhomocysteine (SAH)↓, glutathione (GSH)↓, L-methionine
(Met)↓, homoserine↓
161
Dietary serine and glycine Intestinal cancer Anti-oxidant response↑
restriction Lymphoma
164
Low-protein diet Breast cancer mTORC1 signaling↓, TFEB↑, TFE3↑, mTORC1↑, tumor-associated
macrophages↑
157
Breast cancer IGF-1↓
Melanoma
Low-protein isocaloric diet Melanoma NK cells↑, CD3+ cells↑, CD8+ cells↑ 165
166
High-protein diet Bladder cancer Urinary urea↑, intracellular deposition of ammonia↑, tumor growth↓
167
Overactivation of CRP, MCPT2, MCPT9, EPXH2, SERPING1, SRGN,
CDKN1C, CDK6, CCNB1, PCNA, BAX, MAGEB16, SERPINE1, HSPA2, and
FOS
184
High-salt diet Melanoma The expression of Tnfα, Ifnγ, and Nos2↑
Lung cancer Suppressive function of MDSCs↓
185
Breast cancer IL-12p40↑, ICAM-1↑, IFNγ↑, TNFα↑, macrophages↑, M-MDSCs
Melanoma differentiation into antitumor macrophages↑, functions of PMN-
MDSCs switch from immunosuppressive to proinflammatory and
antitumor↑, CD4+ T cells↑, CD8+ T cells↑, IFNγ+CD4+ T cells↑,
IFNγ+CD8+ T cells↑, Th17 cells↑, TNFα+ Th17 cells↑
IL-6↓, IL-10↓, GM-CSF↓, MDSCs↓, M-MDSCs↓, Tregs↓
Melanoma NK cells↑, CD107a+ NK cells↑, IFNγ+ NK cells↑, Bifidobacterium↑ 183
PD-1+ NK cells↓, CTLA-4↓, PD-1↓

187
Breast cancer Hyperosmotic stress↑, lung metastasis↑
190
Th17 cells↑, the expression of Il17f, Il21, Il22 and Rorγt↑
γENaC mediated chronic inflammatory response↑, RNS/ROS↑, IL-6↑, 191
TNFα↑, tumor growth↑

Xiao et al.
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Table 1. continued
High-fat diet Nonalcoholic steatohepatitis and Hepatic unconventional prefoldin RPB5 interactor (URI) ↑, Th17↑, 199
hepatocarcinogenesis IL-17A↑
Neutrophil infiltration into white adipose tissue, causing insulin
resistance and release of fatty acids
Helicobacter-induced chronic Immature myeloid cells↑, CD4+ T Cells↑, IL-17A↑, granulocyte 200
gastric inflammation and gastric macrophage colony-stimulating factor↑, phosphorylated STAT3↑

carcinogenesis
Colorectal cancer Myeloid cells↑, MDSCs↑, TAMs↑, IL-2+CD8+ T cells↑, triglyceride↑, 207
diglyceride↑
CD8+ T cells↓, leukocyte/tumor cell ratio↓, CD8+ T cells/tumor cell
ratio↓, Ki67+CD8+ T cells↓, CD8+/Treg ratio↓, ICOS+CD8+ T cells↓, PD-
1+CD8+ T cells↓, GZMB+CD8+ T cells↓, fatty acid↓
PD-1highCD4+ T cells↑, PD-1highCD8+ T cells↑ 209
CD4+ T cells↓, CD8+ T cells↓, central memory CD4+ T cell↓, effector

memory CD4+ T cell↓, CD107a+CD4+ T cells↓, CD107a+CD8+ T cells↓,
TNFα+CD4+ T cells↓, IFNγ+CD4+ T cells↓, TNFα+CD8+ T cells↓,
IFNγ+CD8+ T cells↓
IL-6↑, M2-like TAMs↑, CCL20↑, B cells↑, Tregs↑, αβT cells↑, γδT cells↑ 203
296
Total macrophages↑, M2-like macrophages↑
M1-like macrophages↓
212
EVs↑, YAP signaling↑, CYR61↑, M2-like macrophages↑, liver
metastasis↑
Oral squamous cell carcinoma CD45+ cells↑, myeloid cells↑, MDSCs (mainly PMN-MDSCs) ↑, CCR1+ 205
PMN-MDSCs↑, Arg1+ MDSCs↑, the expression of Arg1 and S100a9↑

T cells↓
202
Prostate cancer MDSCs↑, M2/M1 macrophage ratio↑, the expression of Il6, Il1b, Il13,
and Il17a↑, pSTAT3+ cells/tumor cells ratio↑
213
SREBP prometastatic lipogenic program↑, lipid↑
+ + + + + 206
Breast cancer MDSCs↑, effector CD8 T cells↑, PD-1 CD8 T cells↑, Ki-67 CD8
T cells↑, IFNγ+CD8+ T cells↑, apoptotic CD8+ T cells↑, Fas+CD8+
T cells↑, PMN-MDSCs↑, the expression of MDSC-related cyto/
chemokines (Il1b, Cxcl1, Cxcl3, S100a8, and Csf3) ↑, CXCL1↑, per cell
expression of FasL in PMN-MDSCs↑
naïve CD8+ T cells↓, IFNγ↓, Bcl-2+CD8+ T cells↓
201
Overexpression of nitric oxide synthase, NO↑, recruitment of
macrophages↑
211
Palmitate↑, acetyl-CoA↑, lysine acetyltransferase 2a↑, nuclear factor-
kappaB subunit p65 acetylation↑, lung and liver metastasis↑
215
CD36 palmitoylation↑, MUFAs intake↑, palmitate-induced
lipotoxicity↓
208
Colorectal cancer Valine↑, leucine↑
CD45+ cells↓, CD8+ T cells↓, IFNγ+CD8+ T cells↓, IFNγ+TNF+CD8+
T cells↓, GZMB+CD8+ T cells↓, Ki67+CD8+ T cells↓, PD-1+CD8+
T cells↓, CD98+CD8+ T cells↓, pS6+CD8+ T cells↓, glutamine↓,
arginine↓, ornithine↓, kynurenic acid↓
Melanoma CD45+ cells↓, CD8+ T cells↓, CD4+ T cells↓, NK cells↓, CD49d+CD8+
T cells↓, CXCR3+CD8+ T cells↓, the expression pf Cxcl9 and Cxcl10↓,
IFNγ+TNF+CD8+ T cells↓, lipidtox+CD8+ T cells↓
204
Pancreatic cancer TAMs↑, IL-1β↑, IL-4↑, IL-5↑, IL-2↑
+ 210
CD45 cells↑, myeloid cells↑, MDSCs↑, tumor-associated neutrophils↑,
IL-1β↑
Melanoma PD-1+CD8+ T cells↑, Tim3+CD8+ T cells↑, Lag3+CD8+ T cells↑, 246
expression of Cpt1a↑
Ki67+CD8+ T cells↓
217
High-cholesterol diet Colorectal cancer IL-1β↑, IL-6↑, TNFα↑, macrophages↑, NLRP3 inflammasome
activation↑
218
Macrophages↑
IFNγ+CD8+ T cells↓
Hepatocellular carcinoma NK cells↑, NK cells↑, effector function of NK cells↑, CD8+ T cells↑ 221
222
Fish oil high-fat diet (vs. Breast cancer ROS production in TAMs↑
cocoa butter high-fat diet) TAMs↓

Xiao et al.
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Table 1. continued
223
Fish oil high-fat diet (vs. Prostate cancer M1-like macrophages↑
corn oil high-fat diet) M2-like macrophages↓, the expression of CD206, Arg1, TNFα, CCL2,
CCL22, MMP-9, VEGF↓
Safflower oil high-fat diet Breast cancer CD8+ T cells↓, CD4+ T cells↓, TNFα+CD8+ T cells↓, TNFα+CD4+ 224
(vs. olive oil high-fat diet) T cells↓

High-fiber diet Lymphoma DCs↑, cDC1↑, Ifnb1+ monocytes↑, Xcl1 on NK cells↑ 301
Colorectal cancer DCs↑, monocytes↑

Macrophages↓
Furthermore, research has shown that fasting, CR, and caloric of eating patterns, including complete and voluntary deprivation
restriction mimetics (CRMs) can promote T-cell-mediated tumor of food with no restriction on drinking water.129 An FMD is based
cytotoxicity, alter NK cell function, and potentially trigger on a regimen of low-calorie and low-protein foods that mimics the
immunogenic cell death, thereby stimulating cancer immunosur- effects of fasting but induces fewer side effects. This approach
veillance pathways.119 CRMs are pharmacological agents or retains the benefits of traditional fasting methods while minimiz-
natural compounds that imitate the biochemical effects of CR by ing their potential drawbacks.130
reducing the lysine acetylation rates of cellular proteins.120 Fasting or intake of an FMD can cause various metabolic
Examples of CRMs include hydroxycitrate (an inhibitor of ATP changes, including alterations in the systemic levels of hormones
citrate lyase), spermidine (an inhibitor of EP300 acetyl transferase and growth factors such as insulin, glucagon, growth hormone,
activity), and resveratrol (an activator of sirtuin-1 deacetylase IGF-1, glucocorticoids or adrenaline.131 In response to these
activity).121 Treatment with CRMs has been found to decrease the changes, normal cells activate protective mechanisms against
concentration of free IGF-1, promote autophagy in cancer cells, stress and toxic insults, thereby reducing their metabolic
and improve the antitumor immune response, resulting in a requirements and cell division rate. On the other hand, because
reduction in tumor growth when combined with immunogenic fasting or FMDs reduce tumor growth-promoting nutrients and
chemotherapeutics.119 CRM hydroxycitrate has been found to factors, cancer cells struggle to manage metabolite deprivation
stimulate autophagy in U2OS osteosarcoma cells in vitro, thereby and thus develop greater sensitivity to cancer therapies.132 In
increasing antitumor immunosurveillance and reducing tumor obesity-driven postmenopausal cancer mouse models, TRF was
mass in mice with autophagy-competent mutant KRAS-induced shown to delay the onset of tumors and reduce lung metastasis.
lung cancers.122 Moreover, in vitro treatment with resveratrol Moreover, TRF was found to increase systemic insulin sensitivity
inhibits mitochondrial respiration in breast cancer cell lines and decrease hyperinsulinemia. Importantly, TRF could also
through a SIRT1-dependent mechanism, diminishes the expres- restore the circadian rhythm of gene expression within tumors
sion of markers associated with breast CSCs, and promotes their while attenuating both tumor growth and insulin signal transduc-
differentiation.123 Collectively, these findings suggest that CRMs tion.133 Fasting can cause an “anti-Warburg effect” by reducing
may enhance antitumor immunosurveillance in preclinical models. aerobic glycolysis and glutaminolysis while increasing OXPHOS
Moderate physical activity, energy restriction, and their uncoupled from ATP synthesis.134 In cancer cells, OXPHOS
combination can also affect tumor growth. In fact, the combined increases reactive oxygen species (ROS) production and leads to
effects of moderate physical activity and 10% energy restriction oxidative stress, activation of p53 signaling and DNA damage,
(PA + ER) have been shown to significantly delay primary tumor particularly when combined with chemotherapy or other cancer
growth, reduce spontaneous metastases, and prolong survival. therapies.135 Therefore, the unique metabolic vulnerabilities of
These effects on tumor progression and survival are accompanied cancer cells, which differ from those of normal cells, can be
by beneficial changes in immune cell infiltrates within the strategically targeted to develop novel and effective therapeutic
microenvironment. Specifically, the PA + ER combination leads interventions. According to a recent study, the combination of
to an increase in the percentage of CD8+ T cells and a decrease in chemical treatment with an FMD reduces the expression of heme
the percentage of total MDSCs and MDSC subsets within oxygenase-1 (HO-1), which is a stress-responsive enzyme that
tumors.124 protects cancer cells against oxidative damage and apoptosis
Nevertheless, it is crucial to emphasize that there are in vivo. Interestingly, this combination treatment resulted in
established nutritional recommendations for cancer care, and upregulated HO-1 expression in normal cells. The downregulation
the weight loss or reduction in protein intake often associated of HO-1 production in cancer cells, in part, facilitated FMD-induced
with CR may conflict with these guidelines.125 These dietary chemosensitization of cancer cells by boosting CD8+ TIL-
practices could exacerbate the risk of malnutrition, sarcopenia, dependent cytotoxicity, which was possibly facilitated by
fatigue, delayed wound healing, and impaired immunity, particu- decreased Tregs.136 A separate study conducted with mouse
larly in cancer patients who are already at an increased age- models of colon cancer indicated that alternate day fasting for
associated risk for these conditions.126 Therefore, while exploring 2 weeks triggered autophagy in cancer cells, which in turn
dietary interventions for cancer treatment, the potential adverse downregulated CD73 expression. As a result, the production of
effects on overall patient health and nutritional status must be immunosuppressive adenosine in cancer cells was reduced,
carefully considered. ultimately preventing macrophages from acquiring an M2
immunosuppressive phenotype.137
Fasting or fasting-mimicking diet Clinical experiments have suggested that intake of an FMD can
In addition to CR, alternative approaches such as intermittent induce metabolic changes and increase antitumor immunity in
fasting (IF), including short-term fasting (STF), intake of an FMD, cancer patients. In fact, the final outcomes of an FMD-treated
and time-restricted feeding (TRF), which limits food consumption clinical trial (NCT03340935) demonstrated that a severely calorie-
to a specific time window each day, are being condisered.127,128 restricted, five-day FMD regimen was well tolerated and resulted
The term “fasting” has a broad definition, encompassing a range in substantial systemic metabolic changes in patients with

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different tumor types who were concurrently receiving antitumor cells.152 These findings suggest that a KD has the potential to
therapies.138,139 In another clinical trial called DigesT attenuate tumor-induced T-cell suppression by decreasing the
(NCT03454282), a five-day FMD regimen was found to broadly population of cells susceptible to the inhibitory PD-1 pathway.
reshape intratumor immunity in breast cancer patients. Specifi- Although KD has shown various potential benefits to tumor
cally, the FMD was shown to promote the infiltration of activated patients with its promising effects of inhibiting tumor cell growth
and cytotoxic immune cell populations, including total and and activating immune response, there is still limitation in its
activated intratumoral CD8+ T cells, M1-like macrophages, aDCs, clinical application owing to its inevitable side effects.153 It should
and NK cells. These changes were paralleled by an increase in be considered that KD also presents some risks, as they are
immune signatures associated with improved clinical outcomes in typically high in saturated fats and may lack a substantial amount
cancer patients.138 of nutrients, specifically carbohydrates and dietary fiber, as well as
micronutrients such as calcium, magnesium, potassium and
Ketogenic diet vitamins A, B and B6.154,155 According to a recent research, KD
A KD comprises a high-fat component, very low carbohydrate delayed tumor growth but meanwhile accelerated cachexia onset,
levels, and low to moderate protein levels, as explained in a recent therefore shortening survival in a mouse model of IL-6-producing
study.140 A traditional KD is typically formulated at a 4:1 ratio of cancer. Excitingly, the same research group found that applying
fat:carbohydrate plus protein.141 In this classical formulation, dexamethasone during KD treatment might delay cachexia onset
80–85% of calories are derived from fat, 10–15% from protein, without affecting the inhibition of tumor growth, providing
and less than 5% from carbohydrates.142 A KD is known to be fundamental insight into reversing the limitations of the clinical
effective at treating epilepsy, lowering glucose levels, and application of KD.156
producing ketone bodies in vivo.143 There is increasing evidence
to support the use of KD as a potential tumor treatment or Protein restriction diet
prevention method, either as a standalone approach or in The prevailing notion suggests that high protein intake, particu-
combination with other medicines.144 larly among individuals under the age of 65, potentially escalates
The Warburg effect indicates that lower intratumoral glucose the risk of overall and cancer-related mortality.157 To establish a
levels can impede tumor growth, which can be achieved through protein restriction diet, either dietary protein intake or the number
pharmacological intervention and dietary changes such as a KD. of amino acids can be reduced.140 Recent research has demon-
Cancer cells, unable to utilize ketone bodies produced by KD for strated that dietary protein restriction is linked with a reduced
energy due to their aberrant mitochondrial function and incidence of tumor occurrence and a decreased risk of
diminished enzyme activity, can essentially be “starved” of mortality.158
glucose. Hence, KD emerges as a potentially promising strategy Dietary restriction of protein and certain amino acids, including
for cancer prevention.145 One of the primary ways in which a KD serine, methionine, and branched-chain amino acids (BCAAs) such
potentially promotes potential anticancer effects is by increasing as leucine, isoleucine, and valine, has been shown to impede
the levels of β-hydroxybutyrate (β-HB), which is the most tumor growth.159 One mechanism through which protein restric-
abundant ketone body.146 For instance, β-HB has been proven tion may inhibit tumor growth is via the IGF-1 signaling pathway.
to inhibit CRC by activating the transcriptional regulator Hopx In melanoma and breast cancer mouse models, it has been
through the surface receptor Hcar2, thereby reducing the observed that mice fed a low-protein diet (4% kcal protein) exhibit
proliferation of colonic crypt cells and suppressing tumor reduced IGF-1 levels and slower tumor progression compared to
growth.147 Another antitumoral effect of KD is upregulating the those fed a high-protein diet (18% kcal protein). A low-protein diet
expression of the circadian clock gene Per (Period) by activating has been associated with reduced IGF-1 levels in patients aged
AMPK and upregulating SIRT1 (Sirtuin1), resulting in enhanced 50–65 years, subsequently decreasing their risk of death from
apoptosis and growth delay in tumor cells.148 KD also decreases cancer. Conversely, a low-protein diet has been linked with an
insulin-regulated PI3K-Akt-mTOR signaling, which is overactivated increased mortality rate in older patients (aged 65 and above),
in pancreatic neuroendocrine tumors (PanNETs), resulting in suggesting that a life-stage-specific approach to protein intake
decreased blood glucose levels and a suppressive effect on the could optimize healthspan and longevity.157 Other potential
development and progression of PanNETs.149 mechanisms for cancer prevention that are mediated by protein
Emerging evidence suggests that a KD may be a valuable restriction could involve mTOR signaling, amino acid metabolic
clinical tool to enhance T-cell-mediated antitumor immune programming, FGF21, and autophagy.158 In addition to these
responses. In vitro and in vivo studies have shown that KD intake general effects, specific dietary restrictions on certain amino acids,
markedly increased the specific responses of human T cells, such as serine and glycine, have been associated with prolonged
resulting in enhanced CD4+, CD8+, and Treg capacity, as well as survival in mouse models of various tumor types. The mechanisms
augmented T memory cell formation. Under conditions of KD underlying this observed survival benefit could include the
intake, CD8+ T cells undergo metabolic reprogramming to rely on correction of abnormal cellular nucleotide, protein, and lipid
OXPHOS in response to increased ketone bodies, leading to synthesis; improved mitochondrial function; and changes in
enhanced cellular energy and respiratory reserve, potentially epigenetic modifications.160,161
improving their functionality.150 In addition, KD intake prevented The antitumoral effect of a low-protein diet also hinges on
the progression of colon tumors by inducing tumor cell oxidative promoting immunosurveillance against cancer, while the dietary
stress, inhibiting MMP-9 expression, and promoting M2 to M1 restriction of amino acids may adversely affect the metabolic
TAM polarization.151 In a mouse model of malignant glioma, KD reprogramming of the TME in various ways. In multiple mouse
feeding led to significantly enhanced innate and adaptive tumor- models, reducing dietary methionine inhibited tumor growth and
specific immune responses. Mice fed a KD showed increased boosted antitumor immunity by increasing the quantity and
cytokine production (IFNγ, TNF, and IL-2) and greater tumor- cytotoxicity of tumor-infiltrating CD8+ T cells.162 Moreover,
reactive CD8+ T-cell cytotoxicity. Moreover, the mice maintained restricted intake of dietary protein or methionine/cystine has
on a KD presented with a higher number of immune cells and a been shown to modify the infiltration and tumoricidal capacity of
higher ratio of CD4+ T cells to Tregs, while the functionality of the TAMs, leading to a significant increase in tumor-infiltrating CD8+
Tregs was weakened. Feeding mice with the KD resulted in a T cells and a decrease in the number of infiltrating MDSCs.
noteworthy decrease in the expression of immune inhibitory Mechanistically, a protein-restricted diet inhibited mTOR pathway
receptors (PD-1 and CTLA-4) on CD8+ TILs, as well as a reduction activation and increased macrophage acquisition of an antitumor
in the expression of inhibitory ligands (CD86 and PD-L1) on cancer phenotype by increasing the number of macrophages undergoing

Xiao et al.
11
polarization to the M1 type.163 Macrophages might sense diet- development of immune-regulated diseases such as infections
derived cytosolic amino acids via the GTPase Rag, which and cancer.182
subsequently regulates the expression of TFEB, TFE3 and mTORC1 HSD, comprising 4% sodium chloride (NaCl), is recognized as a
when activated.164 Furthermore, an isocaloric diet that moderately robust immunomodulator that is capable of eliciting a substantial
reduced protein intake (by 25%) was shown to trigger an unfolded inflammatory response.183 Indeed, research has shown that high
protein response (UPR) that depended on IRE1α in cancer cells. salt conditions can inhibit tumor growth by enhancing antitumor
The increase in UPR activation, in turn, led to an increase in the immunity, particularly through the modulation of MDSC func-
recruitment of CD8+ T cells and enhanced antitumor immuno- tions.184 According to a recent study, an HSD reduced the
surveillance. Notably, intake of a low-carbohydrate diet did not production of cytokines essential for the expansion of MDSCs and
exert the same effect.165 Although a low-protein isocaloric diet has thus attenuated the accumulation of MDSCs within the tumor
been proven to reduce the concentration of amino acids in tumor niche. As a result, the two primary types of MDSCs acquired
tissues, it remains uncertain whether this reduction is limited to different phenotypes: M-MDSCs differentiated into antitumor
certain amino acids. Thus, further research is needed to explore macrophages, and PMN-MDSCs adopted a proinflammatory
the correlation between a low-protein isocaloric diet and the phenotype, which led to the reactivation of T-cell antitumor
decrease in the levels of specific amino acids in tumors. functions.185 Furthermore, a high salt level has been found to
Interestingly, several studies have shown that high-protein diets induce the transformation of anti-inflammatory Tregs into
may also benefit the restriction of tumor growth or clinical proinflammatory Th1 cells, which led to the secretion of the
outcoming of cancer patients, which seem contradictory to the inflammatory cytokine IFNγ.186 In another study, salt functioned as
findings of the protein restriction diet discussed above. However, an adjuvant that enhanced the effectiveness of anti-PD-1
the underlying mechanisms are totally different. A high-protein immunotherapy in tumor regression. Specifically, an HSD induces
diet increased the production of urinary urea in a tumor protein 53 NK cell-mediated tumor immunity by suppressing PD-1 expression
(TP53)-mutated orthotopic bladder tumor mouse model, leading while increasing IFNγ levels and the serum hippurate concentra-
to the cascade modulation of ammonia in tumor cells, which tion. Notably, hippurate is a microbial benzoate metabolism
induces tumor apoptosis.166 These findings challenge the former product that has been identified as a metabolic marker of effective
hypothesis that high urinary urea concentrations caused by a PD-1 immunotherapy in responsive patients.183 Although the
high-protein diet might serve as a potential carcinogenic factor in major antitumoural effect of HSD is modulating immune cell
the bladder, suggesting the urgent need for further investiga- function, mechanisms other than immunomodulation have also
tion.167 Applying a high-protein diet may improve the overall been discovered. For instance, HSD suppressed tumor growth and
survival of older outpatients with advanced gastrointestinal lung metastasis in a murine model of breast cancer, possibly by
cancer, which may improve the nutritional state of these patients inducing hyperosmotic stress or through mimicking CR.187
with poor digestive system function.168 Nevertheless, despite the potential benefits of salt intake on
Moreover, there have been efforts to develop a series of drugs cancer treatment effectiveness, high salt intake can also lead to
that mimic amino acid restriction. One focus of researchers in the the development of a proinflammatory state, which can negatively
cancer therapy field has been on glutamine metabolism, as cancer impact cancer outcomes.188 High salt intake is a risk factor for
cells rely heavily on glutamine. Glutaminase inhibitors, for various types of cancer in humans, including lung, testicular,
instance, have been shown to decrease tumor burden.169,170 The bladder, renal cell, pancreatic, esophageal, and gastric cancer.182
use of 6-diazo-5-L-oxo-norleucine (DON) promoted antitumor HSD has been shown to induce chronic inflammation, which may
immunity by greatly favoring OXPHOS over glycolysis in CD8+ in turn incite continuous cell proliferation, DNA damage, or cancer
T cells while disrupting the metabolism of cancer cells.171 Notably, transformation. However, whether there is a connection remains
DON showed the ability to significantly inhibit the generation and uncertain.188 IL-17, specifically IL-17A, plays an important role in
recruitment of MDSCs and to reprogram M2-like TAMs into the mechanism of action of HSD. Evidence suggests that high salt
proinflammatory TAMs, which increased tumor antigen cross- intake can induce the differentiation of Th17 cells, a prominent
presentation to T cells and enhanced the efficacy of immune source of IL-17A.189 The overproduction of IL-17A can lead to
checkpoint blockade (ICB).172 In addition, CB-839, which is inflammation and other immune responses that contribute to
considered the most effective glutaminase inhibitor, can be various pathologies. Furthermore, in the case of breast cancer, an
utilized alone or in combination with PD-1 inhibitors to treat solid HSD has been found to promote tumor progression and lung
or hematological malignancies.173–175 As previously mentioned, metastasis, increase the proportion of Th17 cells, and activate the
IDO and TDO are tryptophan catabolism enzymes, and inhibitors MAPK/ERK signaling pathway in breast cancer cells through the
of these enzymes have been developed and evaluated in various secretion of IL-17F. The increase in the secreted IL-17F level results
clinical trials.176 For example, epacadostat is a novel compound in the unregulated expression of protumor genes and the induced
that serves as an IDO1 inhibitor, suppressing systemic tryptophan inflammatory responses, ultimately accelerating the proliferation,
catabolism.177 Both in vitro and in vivo studies have demonstrated migration and invasion of breast tumors.190 In addition, the
that epacadostat can reduce tumor growth and promote the combination of high NaCl concentrations with subeffective IL-17
proliferation of T cells and NK cells.178 Furthermore, cyst(e)inase, a has been proven to reduce reactive nitrogen and oxygen species
glutathione inhibitor that degrades cysteine and cystine, reduces (RNS/ROS) levels and enhance the growth of breast cancer
tumor progression by elevating ROS levels and inducing tumor cells.191,192 Recent research has also demonstrated that intake of
cell-selective ferroptosis.179,180 an HSD can disrupt the development and function of NK cells in
mice.193 Therefore, it can be concluded that dietary salt may exert
High-salt diet dual effects on tumorigenesis, and the contradictory results
HSD has long been considered as a risk factor and trigger of obtained may be due to variations in the effects of high salt
malignancies. However, recent studies have provided new concentrations on tumors in different tissues and during different
insights into the effect of sodium intake. As research continues, phases of tumor development.
it is becoming increasingly clear that salt can accumulate in the
interstitium and modulate immune cell differentiation, activa- Obesity and high-fat diet
tion, and function through the effects of extracellular Obesity, a serious health issue characterized by excessive body fat,
hypersalinity.181 In addition, consumption of a HSD can lead is a known risk factor for multiple types of cancer. It can be
to elevated tissue sodium concentrations and affect immune induced or exacerbated by HFD, characterized by the consump-
responses within microenvironments, ultimately impacting the tion of foods rich in saturated fats and cholesterol.194 Obesity can

Xiao et al.
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induce systemic metabolic disruptions within the body, leading to HFD or diet-induced obesity may induce tumor metastasis. HFD
dyslipidemia, hypercholesterolemia, insulin resistance, alterations has been proven to increase palmitate secretion from alveolar
in hormone levels, and changes in the baseline inflammation type 2 cells and nuclear factor-kappaB subunit p65 acetylation in
status.195 Conversely, a low-fat diet, typically associated with the lung to prepare a premetastatic niche.211 HFD-induced fatty
reduced total fat intake, can potentially lower the risk of certain liver may promote liver metastasis by facilitating the secretion of
types of cancer.196,197 Given that both HFD and obesity are major hepatocyte-derived extracellular vesicles (EVs), which transfer Yes-
factors influencing cancer risk, the forthcoming discussion will associated protein (YAP) signaling-regulating microRNAs, hence
primarily focus on these aspects. By diving deeper into the elevating nuclear YAP expression, CYR61 expression, and M2-like
mechanisms by which HFD and obesity affect cancer develop- macrophage infiltration.212 Another mechanism of HFD-induced
ment and progression, we aim to provide a more comprehensive liver metastasis is the upregulation of NOD-like receptor C4
understanding of this intricate relationship. (NLRC4), which further induces M2-like macrophage activation
Dietary obesity is associated with multiple factors related to and IL-1β processing. An alteration from an indolent to a
cancer occurrence and exacerbation of immune suppression in metastatic state may be stimulated by HFD-induced lipid
tumor niches.198 In the context of obesity, increased hepatic accumulation in prostate tumors, the mechanism of which may
expression of the unconventional prefoldin RPB5 interactor (URI) be related to the sterol regulatory element-binding protein
has been shown to couple nutrient surplus with inflammation, (SREBP)-related prometastatic lipogenic program.213 In addition,
leading to nonalcoholic steatohepatitis (NASH) and consequent it is widely acknowledged that the fatty acid receptor CD36 plays
HCC. This process involves URI-induced DNA damage in hepato- an important role in HFD-related metastasis promotion by
cytes triggering Th17 lymphocyte-mediated inflammation, and enhancing the metastatic potential of CD36+ metastasis-
subsequent IL-17A-induced adipose tissue neutrophil infiltration, initiating cells.214 However, a recent study revealed that CD36
which promotes insulin resistance and hepatic fat accumulation, may prevent palmitate-induced lipotoxicity rather than facilitating
thereby inducing NASH and HCC.199 Notably, obesity also HFD-driven metastasis, suggesting that further investigations of
accelerates Helicobacter felis-induced gastric carcinogenesis by the dual effects of CD36 are needed.215
enhancing the trafficking of immature myeloid cells and the Th17 An elevated cholesterol level is an obesity comorbidity, and
response. This exacerbates proinflammatory immune responses, studies suggest that the effects of obesity on cancer may be partly
characterized by cross-talk between inflamed gastric and adipose mediated by increased cholesterol levels.216 In fact, a high-
tissues, thereby contributing to a protumorigenic gastric cholesterol diet (HCD) alone has been shown to promote
microenvironment.200 macrophage infiltration and significantly enhance the growth of
Diet-induced obesity has been shown to elevate nitric oxide CRC tumors.217 One mechanism by which HCD promotes CRC
(NO) production, which enhances tumor growth. This is progression is through the inhibition of the CD8+ T-cell response.
primarily due to the recruitment of macrophages and the Specifically, macrophages with infiltration driven by HCD can
overexpression of inducible NO synthase as a result of HFD.201 secrete CCL5, which obstructs the activation of CD8+ T cells,
Additionally, in response to HFD intake, IL-6-mediated inflam- thereby facilitating the evasion of immune system surveillance by
mation has been shown to accelerate prostate cancer tumor CRC cells.218 27-Hydroxycholesterol (27-HC) is a crucial mediator of
growth and increase the fraction of MDSCs and the M2/M1 the effects of dietary cholesterol on cancer metastasis. This
macrophage ratio.202 The effects of diet-induced obesity extend oxysterol is synthesized through the action of the CYP27A1
to the microenvironment of colitis-associated CRC. Here, diet- enzyme and is present at high levels in the circulatory system.219
induced obesity has been shown to increase IL-6 expression Oxysterol has been shown to modulate the TME by recruiting
and promote the polarization of macrophages into M2-like immunosuppressive neutrophils to the metastatic niche, facilitat-
macrophages, enhancing the production of CC-chemokine- ing cancer progression.220 However, some studies have reported
ligand (CCL) 20. CCL20 recruits CC-chemokine receptor 6 conflicting findings regarding the effects of high serum choles-
(CCR6)-expressing B cells and γδ T cells, ultimately leading to terol levels on cancer progression. For instance, one study showed
colitis-associated CRC progression.203 In animal models of HFD- that high serum levels of cholesterol attributed to HCD intake
induced obesity, the infiltration rate of TAMs and the expression increased the accumulation of NK cells and promoted their
of cytokines in M2-like macrophages were increased, enhancing effector functions to reduce the growth of liver tumors in mice.221
tumor growth and metastasis. However, ablation of VEGFR-1 However, further studies are needed to understand these
signaling can reverse the abnormal TME associated with obesity conflicting findings.
and reprogram TAMs to promote their acquisition of the M1 In expanding on the relationship between HFD and tumor
phenotype.204 promotion, it is worth noting that the tumor-promoting effect of
The intake of an HFD has been shown to significantly increase HFD is not universal and depends largely on the subtype of fatty
the incidence of oral squamous cell carcinoma (OSCC) by acids involved. Mouse models of breast cancer developed
expanding MDSCs within the local immune microenvironment.205 comparable obesity levels from an HFD of either cocoa butter or
Obesity induced by diet can also trigger the accumulation of PMN- fish oil. However, the consumption of the cocoa butter HFD, which
MDSCs, leading to Fas/FasL-mediated apoptosis of tumor- is high in saturated fatty acids, led to faster mammary tumor
infiltrating CD8+ T cells and causing resistance to immunotherapy growth and increased protumor macrophages and IL-10 expres-
in breast cancer treatment.206 Obesity has been shown to sion while reducing B-cell and CD8+ T-cell infiltration. On the
suppress the infiltration and function of CD8+ T cells, which was other hand, the fish oil HFD, which is rich in omega-3 fatty acids,
linked to decreased chemokine production, reduced fatty acid disrupted the typical obesity-tumor growth link and reduced the
availability, and alterations in amino acid metabolism.207,208 number of protumor macrophages.222 This effect of dietary
Moreover, based on findings from mouse models, obesity reduced omega-3 fatty acids is mediated by host GPR120 and has also
the number and function of CD4+ T cells in the TME of CRC, been shown to inhibit prostate cancer.223 Moreover, oleic acid
leading to a compromised antitumor response of both CD4+ and (OA) and linoleic acid (LA) are the most common unsaturated fatty
CD8+ T cells and ultimately accelerating disease progression.209 acids in dietary oils. While both an HFD rich in OA and an HFD rich
Furthermore, considerable evidence shows that obesity-associated in LA can similarly induce obesity in mice, a diet high in LA
adipocytes in pancreatic ductal adenocarcinoma can secrete IL-1β specifically encourages the growth of mammary tumors. Further-
to attract tumor-associated neutrophils (TANs), which subse- more, an LA-rich HFD can impair antitumor T-cell responses via
quently activate pancreatic stellate cells and contribute to tumor the induction of mitochondrial dysfunction.224 Based on these
growth.210 findings, it appears that modulating dietary oil composition may

Xiao et al.
13
constitute a promising strategy for enhancing immune function in can reshape the TME by increasing the population of CD8+ TILs,
both the prevention and treatment of obesity-associated cancers. macrophages and CD86+ DCs. Mechanistically, the activation of
By carefully selecting and balancing the types of fatty acids in AMPK via KD intake is the key molecular event that promotes
HFDs, it may be possible to reduce the tumor-promoting effects of immunotherapy efficacy. This activated AMPK phosphorylates PD-
obesity while simultaneously increasing immune responses L1 on Ser283, which interrupts its association with CMTM4 and
against tumors. Further research in this area may help to identify results in PD-L1 degradation. Furthermore, AMPK phosphorylates
more precise dietary interventions that can ultimately improve EZH2, which impedes polycomb repressive complex 2 (PRC2),
outcomes for individuals at risk of developing obesity-associated leading to an increase in interferons and antigen-presenting gene
cancers. expression.238
Combining a protein-restricted diet with a vaccine or anti-PD-1
therapy has been shown to significantly inhibit tumor growth and
POTENTIAL ROLE OF DIETARY FACTORS IN CANCER prolong survival.239 Notably, treatment with a methionine-/
TREATMENT cystine-restricted diet significantly increased the number of
Immunotherapy tumor-infiltrating CD8+ T cells and cytotoxic granzyme B+CD8+
Recent studies have highlighted the pivotal influence of the TME T cells, which was further enhanced when combined with
on the efficacy of immunotherapy in cancer treatment.225 immunotherapy.163 Another study confirmed the inhibitory effect
Immunotherapy, recognized as a substantial advance in cancer of dietary methionine restriction on tumor growth and its ability to
treatment, has revolutionized the field of oncology by augmenting synergize with PD-1 blockers to increase tumor control. Mechan-
the body’s innate defenses to effectively target and eliminate istically, this dietary approach reduced the number of metabolites,
malignant cells.226 Various forms of cancer immunotherapy have such as S-adenosylmethionine (SAM), which controls N6-
been developed, including oncolytic virus therapies, cancer methyladenosine (m6A) methylation reactions, in cancer cells. A
vaccines, cytokine therapies, adoptive cell transfer, and ICIs, all reduction in the SAM level altered the m6A modification rate and
of which have shown promise in clinical practice.227 Among these decreased the expression of PD-L1 and V-domain Ig suppressor of
therapies, ICIs are perhaps the most important, as they are T-cell activation (VISTA) in cancer cells.162 Moreover, the enzyme
antibody-based drugs that can eliminate the influence of tumor- cyst(e)inase breaks down cystine and cysteine, thereby bolstering
specific CD8+T cells.228 In particular, ICIs targeting PD-1 or its T-cell-mediated antitumor immunity and inducing ferroptosis in
ligand PD-L1 have demonstrated notable clinical efficacy in the tumor cells when combined with PD-L1 blockade.240 IDO1 is a
treatment of various advanced cancers.229 critical enzyme in the tryptophan–kynurenine pathway and has
Extensive research has been conducted to identify the effects of been identified as a promising immunomodulatory target.241 A
various dietary substances and patterns on tumor growth, phase 1/2 (ECHO-202/KEYNOTE-037) trial evaluating the effective-
metastasis and TME reprogramming, which has led to the ness of the IDO1 inhibitor epacadostat combined with pembro-
consideration of nutritional intervention as a possible strategy lizumab on advanced solid tumors showed a high objective
for increasing the efficacy of tumor treatment230,231 (Tables 2, 3). response rate (ORR) of 40.3% overall and 61.9% in malignant
The decline in T-cell functionality with aging, a widely documen- melanoma patients, demonstrating promising antitumor effi-
ted phenomenon, is linked to a reduced efficacy of anti-OX40 cacy.242 Unfortunately, phase 3 trials failed to confirm these
immunotherapy in murine models.232 CR not only preserves T-cell benefits. The ECHO-301/KEYNOTE-252 trial showed that combin-
function but also improves the response of aged CD4+ T-cell ing epacadostat with pembrolizumab failed to prolong
populations to anti-OX40 therapy.233 When used in combination progression-free survival (PFS) or overall survival (OS) compared
with immunogenic cell death (ICD)-inducing chemotherapy and to pembrolizumab alone in patients with advanced melanoma.243
immunotherapy, CRMs potentially enhance the efficacy of cancer Despite being linked to T-cell dysfunction and poor cancer
treatments through synergistic effects.234 Preclinical studies have prognosis, obesity has paradoxically been shown to enhance the
shown that STF, which serves as an adjunct to various cancer response to anti-PD-1/PD-L1 immunotherapy.244 Recent research
treatments, may bolster antitumor immunity by attenuating suggests that immunotherapy yielded superior outcomes in obese
immunosuppressive conditions and amplifying CD8+ T-cell patients, evidenced by an improved response rate and extended
cytotoxicity.235 For example, an experimental study of non-small PFS and OS, in comparison to lean patients.245 However, obesity
cell lung cancer demonstrated that STF sensitized cancer cells to also promoted tumor growth and T-cell exhaustion, leading to
anti-PD-1 therapy. The antitumor efficacy of combination therapy increased PD-1 expression and dysfunction, partly due to high
was achieved by inhibiting IGF-1-IGF-1R signaling in cancer cells, leptin levels. Despite this outcome, PD-1-mediated T-cell dysfunc-
boosting the intratumoral CD8 cell: Treg ratio in the TME.132 tion in individuals with obesity was found to significantly enhance
Furthermore, intake of an FMD has been shown to enhance the tumor responsiveness to PD-1/PD-L1 inhibitors, as confirmed by
effectiveness of immunotherapy against triple-negative breast preclinical and clinical data.246 Therefore, obesity seems to be a
cancer with low immunogenicity by affecting the TME. Specifically, double-edged sword for cancer immunotherapy, and the under-
intake of an FMD has been shown to reactivate Teff cells that lying mechanisms remain unclear and require further
underwent early exhaustion, shift cancer metabolism from investigation.
glycolytic to OXPHOS, and reduce the collagen deposition rate.236
These effects led to the increased efficacy of anti-PD-L1 and anti- Chemotherapy
OX40 immunotherapy. These results suggest that combining Chemotherapy, a cornerstone of traditional cancer treatment,
immunotherapy with dietary restriction may lead to profound employs drugs to destroy rapidly dividing cells, a defining
synergistic effects. characteristic of cancer.247 Despite its widespread use and
KD also enhances the antitumor effects of PD-1 blockade alone undeniable efficacy in many cases, chemotherapy often has
or in combination with anti-CTLA-4 antibodies. Mechanistically, substantial side effects due to its impact on healthy cells.248
the principal ketone body 3-hydroxybutyrate (3HB) in a KD Additionally, individual responses to chemotherapy can vary
prevented the ICB-mediated upregulation of PD-L1 on myeloid greatly and are influenced by a multitude of factors, including
cells while simultaneously promoting the expansion of CXCR3+ T genetics, tumor characteristics, and, intriguingly, diet.15 A growing
cells.237 Similarly, KD enhanced the effectiveness of anti-CTLA-4 body of research now highlights the role of dietary interventions
immunotherapy by reducing PD-L1 protein levels and augmenting in modulating the effectiveness of chemotherapy, emphasizing
the expression of interferons and antigen presentation-related the need to further understand these interactions for improved
genes. When combined with immunotherapy, the intake of a KD therapeutic outcomes.

Xiao et al.
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Table 2. Preclinical studies showing effects of dietary intervention on cancer therapy
Dietary intervention Cancer type Comparison of Results References

treatment
Calorie restriction Breast cancer Radiotherapy Teff/Tregs ratio↑, PD-1+CD8+ T cells↑ 261
Tregs↓
122
CRM hydroxycitrate Fibrosarcomas Chemotherapy Autophagy in tumor cells↑
Colorectal cancer Tregs↓
Lung cancer
132
Fasting or fasting- Lung cancer Immunotherapy CD8/Treg ratio↑, NK cells↑
mimicking diet Tregs↓, CD19+ B cells↓, PD-1+CD8+ T cells↓, PD-1+CD4+
T cells↓
251
Pancreatic cancer Chemotherapy Levels of equilibrative nucleoside transporter (hENT1) in
tumor cells↑
Levels of ribonucleotide reductase M1 (RRM1) in tumor
cells↓
252
Breast cancer Chemotherapy ROS in tumor cells↑
+ + + + + 236
Immunotherapy T cells↑, CD8 T cells↑, GZMB CD8 T cell↑, Ki67 CD8
T cells↑, γδ T cells↑, GZMB+ γδ T cells↑, Ki67+ γδ T cells↑,
Ki67+FOXP3-CD4+ T cells↑, OX40+FOXP3-CD4+ T cells↑,
PD-1+FOXP3-CD4+ T cells↑, Ki67+ Tregs↑, OX40+ Tregs↑,
PD-L1+ PMN-MDSCs↑, macrophages↑, PD-L1+
macrophages↑, ToxintCD8+ T cells↑, ToxintPD-
1intCD39lowCD8+ T cells↑
PMN-MDSCs↓, M2-like macrophages↓
265
Endocrine therapy Circulating IGF1, insulin, and leptin levels↓, AKT-mTOR
signaling↓
Breast cancer Chemotherapy CD8+ T cells↑, CD3+ T cells↑, granzyme-B↑ 136
Melanoma HO-1↓, Tregs↓

266
Lung cancer TKIs E2F-dependent transcription inhibition↑
Breast cancer MAPK signaling pathway↓
Colorectal cancer
267
Hepatocellular TKIs Glucose↓, AKT/mTOR signaling↓
carcinoma
253
Fasting-mimicking diet+ Colorectal cancer Chemotherapy Reactive iron and oxygen species in tumor cells↑
vitamin C
254
Fasting-mimicking diet+ Colorectal cancer Chemotherapy Autophagy in tumor cells↑
ferroptosis inducer
Ketogenic diet Colorectal cancer Immunotherapy IFNγ+CD8+ T cells↑, TNFα+CD8+ T cells↑ 238
258
Neuroblastoma Chemotherapy Tumor burden↓
259
Chemotherapy Serine, glutamine and glycine↑
Tumor blood-vessel density and intratumoral
hemorrhage↓, serum levels of essential amino acids↓
260
Pancreatic cancer Chemotherapy Tumor NADH levels↑
263
Radiotherapy Oxidative stress in tumor cells↑
268
PI3K inhibitors Hyperglycemia↓, insulin secretion↓, mTORC1 signaling↓
262
Lung cancer Radiation or radio- Oxidative stress in tumor cells↑
chemotherapy
Dietary restriction of Prostate cancer Immunotherapy CD8+ T cells↑, CD8+ T cells/M1-like ratio↑, CD8+ T cells/M2- 163
protein/80% methionine- like ratio↑, CD8+ T cells/M-MDSC ratio↑, CD8+ T cells/PMN-

restricted diet MDSC ratio↑
M2-like TAMs↓
Dietary methionine Colorectal cancer Immunotherapy CD8+ T cells↑ 162
restriction Colorectal cancer Radiotherapy Alterations in one-carbon metabolism 264
Soft-tissue sarcoma Antimetabolite

chemotherapy.
269
Dietary serine deprivation Lung cancer Biguanide treatment Serine↓, glycolysis↓
Colorectal cancer
High-salt diet Breast cancer Immunotherapy CD4+ T cells↑, CD8+ T cells↑ 185
Melanoma
Melanoma Immunotherapy PD-1+ NK cells↓ 183

Xiao et al.
15
Table 2. continued
Dietary intervention Cancer type Comparison of Results References
treatment
206
High-fat diet Breast cancer Immunotherapy PMN-MDSCs↑, the expression of Cxcl1↑
+ + + + 246
Melanoma Immunotherapy CD3 T cells↑, CD8 T cells↑, CD8 /CD4 ratio↑
442
Ovarian cancer Chemotherapy Fibrosis↑, M1-like macrophages↓, M2-like macrophages↓,
M2/M1 macrophage ratio↑
Inulin gel Colorectal cancer Immunotherapy CD8+ cells↑, AH1 tetramer+CD8+ T cells↑, DCs↑, CD4+ 303
T cells↑, Tcf1+PD-1+CD8+ T cells↑, neutrophils↑, M1/M2

macrophages ratio↑
PD-1+CD8+ T cells↓, M2-like macrophages↓, Tregs↓
Pectin Colorectal cancer Immunotherapy CD4+ T cells↑, CD8+ T cells↑, IFNγ+CD8+ T cells↑ 304
Due to their expression of oncogenes, cancer cells are more Radiotherapy

susceptible to the effects of fasting and CR than are normal cells, Dietary interventions have emerged as promising strategies for
an effect termed ‘differential stress resistance’.14,249,250 Based on enhancing the efficacy of radiotherapy in cancer treatment. For
this characteristic, CRM hydroxycitrate has been shown to instance, CR combined with radiotherapy, has been shown to
increase sensitivity to chemotherapy by eliciting an adaptive modulate the TME in a triple-negative breast cancer model by
cellular immune response, resulting in a decrease in the number decreasing the number of intratumoral Tregs, increasing the CD8+
of tumor-infiltrating Tregs into the tumor niche in various tumor cell: Treg ratio, and upregulating PD-1 expression on CD8+ T cells.
models.122 Furthermore, compared with patients who received radiotherapy
Emerging research also suggests a profound influence of alone, breast cancer patients who underwent CR concurrently with
fasting or FMD on the efficacy of chemotherapy. In vitro studies radiotherapy exhibited a significant reduction in the serum levels
indicate that fasting cycles not only retard tumor growth but of immunosuppressive cytokines, suggesting potential benefits of
also sensitize a wide array of cancer cell types to chemother- CR in mitigating radiation-induced immunosuppression.261
apy.14 This heightened sensitivity has been observed in various When combined with radiation or radiochemotherapy, KD slows
contexts, including the enhancement of gemcitabine efficacy in tumor growth in lung cancer xenografts, potentially through a
mice with prostate cancer xenografts and the increased efficacy mechanism involving increased oxidative stress.262 Additionally,
of chemotherapy in triple-negative breast cancer via the KD was shown to enhance radiation sensitivity in a pancreatic
upregulation of ROS.251,252 FMD combined with vitamin C can cancer xenograft model, suggesting potential improvements in
potentially increase the effectiveness of chemotherapy for therapeutic outcomes. However, phase 1 clinical trials in patients
treating KRAS-mutant cancer cells by reversing the vitamin with locally advanced non-small cell lung cancer and pancreatic
C-induced upregulation of HO-1 and ferritin.253 Furthermore, cancer showed suboptimal compliance with the diet, indicating
when combined with a ferroptosis inducer, FMD can effectively challenges in practical application.263
eliminate slow-cycling, chemotherapy-resistant cells, suggesting Moreover, other dietary restrictions, such as methionine
a potential strategy for enhancing the sensitivity of certain deprivation, have shown promising results in enhancing the
difficult-to-treat cancers to chemotherapy through dietary efficacy of radiation and antimetabolite chemotherapy. In patient-
interventions.254 Interestingly, fasting can also counteract derived xenograft and autochthonous tumor mouse models,
certain adverse effects of chemotherapy. For instance, it has methionine restriction sensitized tumor cells to these treatments,
been demonstrated to enhance self-renewal in hematopoietic possibly via alterations in one-carbon metabolism.264
stem cells and mitigate the immunosuppression induced by
cyclophosphamide chemotherapy in mice.255 In tumor-bearing Other therapies
mice, both prolonged fasting and FMDs can induce specific In hormone receptor-positive breast cancer mouse models,
stress resistance responses, enhancing chemotoxicity in cancer periodic fasting or an FMD can enhance the therapeutic effects
cells while protecting normal cells.256 This dual action is partly of endocrine agents such as tamoxifen and fulvestrant. This
mediated by the reduction in IGF-1 and glucose levels, thus enhancement is believed to occur through a reduction in
shielding normal cells and organs from chemical toxicity.250 The circulating IGF1, insulin, and leptin levels and suppression of
potential of FMD in clinical settings has been supported by the AKT-mTOR signaling. Concurrent administration of these dietary
‘DIRECT’ study involving HER2-negative stage II/III breast cancer strategies with a therapeutic regimen of fulvestrant and palboci-
patients. This study revealed that treatment with FMD, clib has been associated with prolonged tumor regression and
administered three days prior to and during neoadjuvant reversal of treatment resistance. Analogous metabolic alterations
chemotherapy, enhanced therapeutic efficacy without increas- found in patients on an FMD during estrogen therapy suggest the
ing toxicity or reducing chemotherapy-induced DNA damage in potential of diet as an adjuvant in treating hormone receptor-
T cells.257 Collectively, these findings highlight the potential of positive breast cancer.265
fasting and FMD as adjuncts to chemotherapy, warranting In addition to their effects on hormone-driven cancers, fasting
further exploration and clinical testing. or FMD has also been shown to enhance the efficacy of tyrosine
In addition to slowing tumor growth, KD also sensitizes tumor kinase inhibitors (TKIs) across different cancer cell lines. Mechan-
cells to classic chemotherapy. For example, the combination of KD istically, these effects are attributed to the increased ability of TKIs
with metronomic cyclophosphamide significantly enhances anti- to block cancer cell growth and inhibit the MAPK signaling
tumor effects, resulting in the regression of neuroblastoma pathway under starvation conditions.266 Another study reported
tumors.258,259 Similarly, in pancreatic cancer, cotreatment with that in HCC cells, xenografts, and patient-derived organoids,
KD and cytotoxic chemotherapy substantially elevates tumor fasting improved the therapeutic response to sorafenib through
NADH levels, synergistically suppressing tumor growth and the regulation of glucose transporters and proapoptotic protein
tripling survival benefits compared to chemotherapy alone.260 expression by p53.267

Xiao et al.
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Table 3. Clinical trials of dietary intervention combined with cancer treatment
Dietary intervention NCT Therapeutic intervention Disease Status
Calorie restriction NCT01819233 Surgery and radiotherapy Stage 0-I breast cancer Completed
NCT02792270 Pre-operative radiotherapy Sarcoma Unknown
NCT01802346 Chemotherapy Breast or prostate cancer Recruiting
Cyclic, 5-day calorie restriction NCT05703997 Atezolizumab Small cell lung cancer Not yet
recruiting
Calorie restriction and exercise NCT03131024 Anthracycline-containing Breast cancer Completed
chemotherapy
Intermittent calorie restriction and NCT05359848 Chemotherapy Cancer Recruiting
plant-based diet
Low-carbohydrate diet NCT02149459 Radiotherapy with or without Recurrent brain cancer Unknown
metformin
Very low carbohydrate diet NCT04035096 High dose intravenous vitamin C Stage IV colon cancer with KRAS and Unknown
BRAF mutation
Intermittent fasting NCT01175837 Chemotherapy Cancer Completed
NCT02607826 Chemotherapy Solid tumors Unknown
NCT06015087 Chemotherapy Breast cancer Recruiting
NCT01304251 Chemotherapy Breast cancer Completed
NCT05722288 Radiotherapy and/or chemotherapy Prostate, cervical or rectal cancer Recruiting
and/or hormone therapy
NCT04247464 Chemotherapy Colorectal cancer Enrolling
by
invitation
Nightly fasting NCT05023967 Chemotherapy and metformin Early breast cancer Recruiting
Prolonged nightly fasting NCT05083416 Immunotherapy Advanced head & neck cancer Active, not
recruiting
Alternate day fasting NCT05990426 Chemotherapy Endometrial, ovarian, fallopian tube or Not yet
primary peritoneal cancer recruiting
5:2 intermittent fasting NCT05861362 Radiotherapy Breast Cancer Completed
Time restricted eating with or without NCT05259410 Chemotherapy Breast Cancer Recruiting
Mediterranian diet
Intermittent fasting or vegan diet NCT03162289 Chemotherapy Gynecological cancer Active, not
recruiting
Intermittent fasting or Mediterranian NCT02710721 Chemotherapy with or without Advanced metastatic prostate cancer Completed
diet hormone therapy
Fasting-mimicking diet NCT03595540 Active cancer treatment Cancer Completed
NCT03709147 Metformin hydrochloride, cisplatin, Advanced LKB1-inactive lung Unknown
carboplatin, pemetrexed, adenocarcinoma
pembrolizumab
NCT05763992 Chemoimmunotherapy Triple-negative breast cancer Recruiting
NCT05503108 Neoadjuvant chemotherapy (ddAC, T) HR+, HER2- breast cancer Recruiting
NCT02126449 Neoadjuvant chemotherapy (AC>T) HER2- breast cancer Completed
NCT04248998 Neoadjuvant chemotherapy (AC>T) Triple-negative breast cancer Active, not
with or without metformin recruiting
NCT03340935 Standard cancer treatment Malignancies with the exception of Completed
small cell neuroendocrine tumors
NCT05921149 Carboplatin and paclitaxel Advanced or recurrent ovarian, Not yet
fallopian tube and primary peritoneal recruiting
cancer
Ketogenic diet NCT05119010 Nivolumab and ipilimumab Metastatic renal cell carcinoma Recruiting
NCT05938322 Neoadjuvant radiotherapy Locally advanced nonmetastatic rectal Not yet
adenocarcinoma recruiting
NCT04316520 Nivolumab + ipilimumab, Metastatic renal cell carcinoma Recruiting
pembrolizumab + axitinib, sunitinib or
pazopanib
NCT03962647 Letrozole Early-stage ER+, HER2- breast cancer Active, not
recruiting
NCT03535701 Paclitaxel Stage IV breast cancer Completed
NCT05234502 Neoadjuvant chemotherapy (AC>T) Breast cancer Not yet
recruiting

Xiao et al.
17
Table 3. continued
NCT05708352 Chemotherapy and/or radiotherapy Glioblastoma Recruiting

NCT03451799 Radiotherapy and temozolomide Glioblastoma Active, not
recruiting
NCT02302235 Radiotherapy and temozolomide Glioblastoma multiforme Completed
NCT02939378 Chemotherapy Recurrent glioblastoma multiforme Unknown
NCT04631445 Nab-paclitaxel, gemcitabine, and Metastatic pancreatic ductal Recruiting
cisplatin adenocarcinoma
NCT02516501 Radio(chemo)therapy Breast, head & neck or colorectal Completed
carcinoma
NCT02983942 Chemotherapy (HD-MTX) Primary central nervous system Unknown
lymphoma
Energy restricted ketogenic diet NCT01535911 Chemotherapy and radiotherapy Glioblastoma multiforme Active, not
recruiting
Intermittent fasting and time-restricted NCT04730869 Chemoradiotherapy and adjuvant Glioblastoma multiforme Recruiting
modified ketogenic diet between fasts chemotherapy
Modified ketogenic diet or medium NCT03075514 Chemotherapy, radiotherapy or Glioblastoma Completed
chain triglyceride ketogenic diet chemoradiotherapy
Modified Atkins diet NCT02768389 Bevacizumab Recurrent glioblastoma or other grade Completed
IV malignant glioma
NCT03278249 Temodar and radiotherapy Primary malignant glioma Active, not
recruiting
Low protein diet NCT03329742 Sipuleucel-T Metastatic castrate-resistant prostate Completed
cancer
NCT05356182 Immunotherapy Solid tumors Recruiting
High protein diet NCT05677958 Chemo(radio)therapy or Colorectal or non-small cell lung Completed
immunotherapy cancer
NCT03559881 Chemotherapy and/or immunotherapy Non-small cell lung cancer Completed
Supplementation of poly-unsaturated NCT04965129 Immunotherapy, chemotherapy and Non-small cell lung cancer Recruiting
n-3 fatty acids and high-protein diet tyrosine kinase Inhibitors
Mediterranean diet NCT04045392 Adjuvant hormone therapy Breast cancer Unknown
NCT04534738 Chemotherapy Cancer Completed
Mediterranean diet with or without NCT05839210 Chemotherapy Lymphoma Recruiting
exercise
Plant-based Mediterranean diet (olive NCT01083771 Androgen deprivation therapy Prostate cancer Completed
oil supplementary)
Mediterranean-DASH intervention for NCT05984888 Chemotherapy, targeted therapies or HR+ breast cancer Recruiting
neurodegenerative delay endocrine therapy
High-fiber diet NCT05805319 Immune checkpoint inhibition Non-small cell lung cancer Recruiting
NCT04534075 Radiotherapy Gynecological, colorectal, anal, Recruiting
prostate, or urinary bladder cancer
NCT01549782 Radiotherapy Gynecological cancer Completed
NCT00888147 Radiotherapy Head & neck cancer Completed
Low-fiber diet or high-fiber diet NCT01170299 Radiotherapy Gynecological, urological (bladder), Completed
colorectal or anal cancer
Isocaloric high-fiber diet NCT04645680 Pembrolizumab or nivolumab Unresectable melanoma Recruiting
High-fiber, plant-based diet and NCT04866810 ipilimumab + nivolumab, Melanoma Recruiting
exercise relatlimab + nivolumab,
pembrolizumab or nivolumab
Calorie-restricted plant-based diet and NCT04298086 Anastrozole, letrozole or exemestane HR+ breast cancer Active, not
exercise recruiting
Low fat diet NCT00002564 Adjuvant therapy with or without either Early-stage breast cancer Completed
chemotherapy or endocrine therapy
Carbohydrate-restricted, high-fat diet NCT04253808 Radiotherapy Head & neck cancer Completed
Oral vitamins A and E NCT00228319 Chemotherapy Ovarian cancer Completed
Oral vitamin A and folic acid NCT05720559 Oxaliplatin, cetuximab and Prehepatic CTC+ colorectal cancer Not yet
metronidazole recruiting
NCT05774964 Oxaliplatin, cetuximab and Colorectal cancer with liver Not yet
metronidazole metastases recruiting
Vitamins B6 and B12 supplementation NCT00659269 Chemotherapy Cancer Completed

Xiao et al.
18
Table 3. continued
Vitamin B12 and folic acid NCT02679443 Chemotherapy Non-small cell lung cancer Completed
supplementation NCT00609518 Pemetrexed and dexamethasone Non-small cell lung cancer Completed
NCT00216099 Pemetrexed Hormone refractory prostate cancer Completed
Oral vitamin D NCT03467789 Radiotherapy Basal cell carcinoma Recruiting
NCT04864431 Chemotherapy Epithelial ovarian cancer Recruiting
NCT02603757 Chemotherapy Colorectal cancer Completed
NCT04091178 Chemotherapy Breast cancer Completed
NCT04677816 Chemotherapy Triple-negative breast cancer Recruiting
NCT03331562 Pembrolizumab Metastatic pancreatic ductal Completed
adenocarcinoma
Oral vitamin D and Omega-3 NCT05331807 Chemotherapy Breast cancer Recruiting
Oral vitamin E NCT03613389 Chemotherapy Pediatric cancer Unknown
NCT00363129 Chemotherapy Cancer Completed
Oral vitamin E and Hydrogen-rich NCT04713332 Radiotherapy Rectal cancer Unknown
water
Antioxidant-deficient diet NCT00486304 Chemotherapy and radiotherapy Oropharyngeal cancer Completed
Anti-inflammatory diet NCT03994055 Chemo-radiotherapy and Cervical cancer Active, not
brachytherapy recruiting
Low copper diet NCT00003751 Radiotherapy and penicillamine Glioblastoma multiforme Completed
Paleolithic diet and exercise NCT04574323 Radiotherapy Breast cancer Completed
Low-residue diet NCT00258401 Radiotherapy Uterine, cervical or prostate cancer Completed
KD has also shown promise in supporting the effectiveness of host. The constituents of the gut microbiome and their interac-
phosphatidylinositol 3 kinase (PI3K) inhibitors and overcoming tions with the host immune system can impact the development
drug resistance in various mouse cancer models, including of tumors and carcinogenesis.271 Various dietary patterns have
pancreatic, bladder, endometrial, and breast cancer models, as been found to significantly influence the composition and
well as acute myeloid leukemia.145 KD appears to enhance this functionality of the gut microbiome.272,273 It is through these
effectiveness by decreasing hyperglycemia and reducing insulin changes in the gut microbiome that dietary patterns can indirectly
secretion, actions correlated with a decrease in mTORC1 signaling influence the outcomes of cancer patients.274
within the tumor.268 In recent early studies, several interventional strategies, ranging
Finally, the combination of serine deprivation and biguanide from dietary interventions to fecal microbiome transplant (FMT)
treatment, such as phenformin and metformin, can lead to and prebiotic, probiotic and antibiotic treatments, have shown
metabolic stress in cancer cells. This stress arises from the forced promise in altering the composition or functional capacity of the
upregulation of glycolysis due to the biguanide-induced reduction gut microbiome.275 Two prospective cohort studies have sug-
in OXPHOS. Under conditions of serine deficiency, this stress may gested that diet-related inflammation can alter the gut micro-
exceed the metabolic flexibility of cancer cells, leading to their biome, leading to the development of CRC by suppressing
potential death and, consequently, enhanced anticancer adaptive antitumor immune responses.276,277 Other prospective
effects.269 cohort studies have revealed the associations between prudent
In summary, these findings underscore the potential of dietary diets (rich in whole grains and dietary fiber) and Western diets
interventions to modulate the therapeutic landscape of cancer (rich in red and processed meat, refined grains, and desserts) with
treatment, enhancing the effectiveness of drugs and potentially CRC risk and indicated that the effect of these diets may differ
overcoming resistance mechanisms. However, it should be viewed based on the presence of Fusobacterium nucleatum in tumor
with cautious optimism. The biological plausibility of diet tissue.278,279 Specifically, these studies showed that, compared
modifying treatment efficacy and resistance is compelling; with a Western diet, adhering to a long-term prudent diet is
however, the translation of this concept into clinical practice associated with a reduced risk of F. nucleatum-positive CRC;
requires rigorous validation. It is critical to remain grounded in however, it does not appear to mitigate the risk of F. nucleatum-
evidence-based medicine, recognizing that dietary strategies are negative CRC.278 A recent study investigated the impact of the gut
adjuncts, not replacements, for established therapeutic regimens. microbiota and dietary patterns on the response to ICIs in patients
Further exploration and clinical validation are necessary to fully with melanoma. The present study revealed that patients with
understand these interactions and to integrate dietary strategies microbiomes dominated by the Ruminococcaceae family had
into standard cancer care effectively and safely. greater response rates than did those with microbiomes
dominated by the Bacteroidaceae family. Furthermore, another
finding revealed that a poor response was associated with
DIET CHANGES THE GUT MICROBIOME IN CONJUNCTION WITH decreased intake of fiber and omega-3 fatty acids.280 These
ANTITUMOR EFFECTS AND CANCER TREATMENT results suggest that dietary interventions may be promising for
The gut microbiome encompasses the genetic makeup of all improving cancer treatment outcomes.
species within the gut, such as bacteria, viruses, yeasts, Accumulating data suggest that alterations in the gut micro-
protozoans, fungi, and archaea, and can be affected by a range biome primarily contribute to the progression, prognosis, and
of internal and external factors.270 The gut microbiota plays a treatment of cancer, primarily through interactions with the
significant role in influencing the health and disease status of the immune system. Metabolites produced by the microbiota play

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19
important roles in modulating antitumor immunity.281,282 promote dysplasia and carcinogenesis by modulating the
Microbiota-derived metabolites have been demonstrated to esophageal microenvironment and gut microbiome, thereby
influence the efficacy of tumor immunotherapy. Short-chain fatty inducing inflammation and promoting stem cell proliferation.294
acids (SCFAs) are produced primarily by the fermentation of The bile salt hydrolase (BSH) enzyme expressed by Bacteroides
nondigestible carbohydrates, such as dietary fiber, by the was also found to play a crucial role in CRC progression in
microbiota. The main SCFAs include acetate, propionate, and overweight patients and in model mice with HFD-induced CRC.
butyrate.283,284 The gut microbiota, which is mediated by SCFAs, High BSH activity activates the β-catenin/CCL28 axis, resulting in
can potentiate the antitumor activity of CD8+ T cells, thereby an increase in immunosuppressive Tregs and accelerated CRC
influencing the efficacy of tumor immunotherapy both in vitro progression.295 Moreover, HFD feeding can reduce the level of
and in vivo.285 Metabolic and epigenetic reprogramming enables SCFA-producing bacteria and the rate of SCFA production, leading
pentanoate and butyrate to enhance the effectiveness of cancer to decreased levels of SCFAs that can activate the MCP-1/CCR2
immunotherapy by boosting the antitumor activity of antigen- axis. This effect promotes M2 TAM recruitment and polarization,
specific cytotoxic T lymphocytes and ROR1-targeting chimeric ultimately contributing to CRC progression.296
antigen receptor (CAR)-T cells.286 Inosine is another important Studies suggest that the gut microbiota plays a crucial role in
metabolite produced by the microbiome and is closely associated modulating the therapeutic response to immunotherapy.297,298 In
with immunotherapy. Intestinal Bifidobacterium pseudolongum fact, specific gut microbial signatures have been shown to
promoted Th1 cell transcriptional differentiation and antitumor differentiate responders from nonresponders across various
activity to increase the efficacy of immunotherapy, mainly through epithelial tumor types in cohorts treated with ICB.299 Considering
the action of inosine.287 Inosine is instrumental in enhancing the profound impact of the gut microbiota on the immune
antitumor therapy by serving as a carbon source for CD8+ T cells system, research investigating the modulation of the gut
in glucose-restricted microenvironments, facilitating their growth microbiota via dietary interventions to optimize cancer treatment
and optimal functioning.288 Moreover, engineered bacteria can efficacy has been predominantly centered around immunother-
modify the concentration of metabolites in the microenvironment, apy. A high-fiber dietary intervention has been associated with
thereby altering the composition of the TME. For instance, the significantly prolonged PFS in melanoma patients receiving ICB
genetically engineered probiotic strain Escherichia coli Nissle 1917 treatment.300 Microbiota-derived STING agonists, specifically c-di-
colonizes tumor sites and continuously converts ammonia AMP, induce the production of type I interferon (IFN-I) in
metabolites into L-arginine. When injected into the tumor, this intratumoral monocytes. This activation results in the transforma-
strain has been shown to increase the concentration of L-arginine tion of mononuclear phagocytes within the TME into immunos-
within the microenvironment, leading to increased infiltration of timulatory monocytes and DCs. Additionally, it promotes the
tumor-infiltrating T cells, sustained effector T-cell functions, polarization of macrophages to antitumor macrophages and
increased tumor-specific T-cell memory formation, and enhanced stimulates crosstalk between NK cells and DCs. A high-fiber diet
efficacy of PD-L1-blocking antibodies.289 can trigger this mechanism by enriching the population of
Recent research has highlighted the role of the gut microbiota Akkermansia muciniphila, which produces c-di-AMP and enhances
in the antitumor effects of dietary intervention (Fig. 3). Specifically, the therapeutic effect of ICB in melanoma patients.301 The
enrichment of Bifidobacterium bifidum after CR increases acetate presence of Akkermansia, a mucin-degrading bacterium, is
levels, which in turn elevates IFNγ+CD8+ T cells in the TME. In strongly associated with favorable outcomes in cancer patients.302
contrast, the antitumor effect of IF was not mediated by the gut Moreover, inulin, a polysaccharide dietary fiber, can enhance the
microbiome, as it was not abrogated after the microbiota was effectiveness of anti-PD-1 therapy by increasing the abundance of
depleted.290 Similarly, recent studies have revealed that KD beneficial commensal microbiota genera (e.g., Akkermansia,
significantly influences the gut microbiota, inducing a shift from Lactobacillus and Roseburia) and SCFAs, further increasing the
a population dominated by tolerogenic bacteria (Lactobacilli spp., number of stem-like T-cell factor-1 (Tcf1)+PD-1+CD8+ T cells.303
Clostridium asparagiforme) toward a population dominated by an Similarly, oral administration of pectin, another dietary poly-
increase in immunogenic bacteria (such as Akkermansia mucini- saccharide fiber, can largely improve the efficacy of anti-PD-1
phila).237 It has been reported that a shift in the gut microbiota is mAbs by increasing the number of butyrate-producing bacteria,
partially attributable to the host’s production of ketone bodies which is sufficient to promote T-cell infiltration and activation in
due to the intake of a KD. Among these ketone bodies, β-HB the TME.304
selectively suppresses the proliferation of Bifidobacterium. This Although research into the antitumor or protumor effects of the
suppression subsequently leads to a reduction in intestinal Th17 intratumor microbiome is still in its early stages, recent studies
immune cells.291 Dietary methionine/cystine restriction has been have started to focus on how the intratumor microbiome can
shown to alter the gut microbiota and potentially contribute to influence the effectiveness of immunotherapy. The colonization of
immune system alterations. Specifically, this type of diet restriction Bifidobacterium in the microenvironment, combined with anti-
promoted a significant decrease in the relative abundance of CD47 monoclonal antibody treatment, stimulates the STING
multiple Ruminococcaceae and Prevotellaceae families while signaling pathway and enhances the cross-priming of DCs to
increasing the presence of members of the Lactobacillaceae upregulate CD8+ T cells.305 The probiotic Lactobacillus reuteri (Lr)
family.163 Consumption of an HSD promotes an increase in the within melanoma promotes the local generation of IFNγ by CD8+
abundance of Bifidobacterium, which, due to enhanced gut T cells through the release of its tryptophan breakdown
permeability, infiltrates tumors, subsequently augmenting the metabolite, indole-3-aldehyde (I3A), thus enhancing ICI efficacy.
functionality of NK cells and ultimately contributing to tumor Dietary intake rich in tryptophan boosts the antitumor immunity
regression. These results suggest that HSD intake modulates the induced by Lr and ICI, which is dependent on the CD8+ T-cell AhR
gut microbiome, which may stimulate NK cell-dependent tumor signaling pathway.306
immunity, thereby providing potential implications for the Apart from immunotherapy, recent research has also started to
development of novel therapeutic interventions.183 The intake of investigate how diet, by influencing the gut microbiota, could
HSD has also been shown to inhibit enterotoxigenic Bacteroides affect other forms of cancer treatment. By enriching the gut
fragilis (ETBF)-promoted colon carcinogenesis by decreasing the microbiome with queuosine-producing bacteria, HFD can induce
expression of IL-17A and iNOS, thereby inhibiting inflammation.292 chemotherapy resistance in pancreatic cancer through the
However, intake of an HSD can exacerbate Helicobacter pylori upregulation of the oxidative stress protector PRDX1. This
infection, contributing to gastric carcinogenesis.293 In a mouse resistance can be counteracted by SAM, which is typically
model of Barrett’s esophagus, feeding an HFD was observed to produced by bacteria in lean diets, highlighting the influence of

Xiao et al.
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a f
Bifidobacterium bifidum DCs

TME
CR beneficial
acetate mononuclear ICB efficacy commensal
phagocytes microbiota
reprogramming SCFAs
inulin
macrophage
polarization
crosstalk of
NK cells and DCs
anti-PD-1
IFNγ+CD8+ T cells efficacy
Akkermansia muciniphila
b
ketone bodies tolerogenic c-di-AMP
High-fiber Diet
bacteria
KD Tcf1+PD-1+CD8+ T cells
β-HB immunogenic
bacteria
Bifidobacteria
butyrate-producing
pectin bacteria
T cells infiltration
T cells activation
ICB efficacy
intestinal Th17 cells
c d e
SCFAs-producing bacteria Lactobacillus reuteri
HSD HFD Tryptophan
Bacteroides fragilis Bifidobacterium
Bacteroides
IL-17A& iNOS SCFAs Bacteroides

BSH enzyme I3A
Helicobacter pylori queuosine-producing β-catenin/CCL28 MCP-1/CCR2

bacteria axis axis 3-IAA
colon
intratumor localization CRC progression
carcinogenesis
chemotherapy
gastric M2 TAM chemotherapy
NK cells resistance Treg cells ICB efficacy IFNγ+CD8+ T cells
carcinogenesis recruitment efficacy
Fig. 3 Mechanisms by which diet modulates antitumor effects and cancer treatment via modulation of the gut microbiome. a Calorie restriction (CR)
elevates IFNγ+CD8+ T cells in the tumor microenvironment (TME) by enriching Bifidobacterium bifidum and increasing acetate levels. b Ketogenic diet
(KD) induces a shift from tolerogenic (Lactobacilli spp., Clostridium asparagiforme) toward immunogenic bacteria (such as Akkermansia muciniphila)
driven by host production of ketone bodies, of which β-HB selectively inhibits the growth of bifidobacteria, resulting in KD-associated decreases in
intestinal Th17 cell levels. c High-salt diet (HSD) increases the abundance of Bifidobacterium and leads to intratumoral localization of Bifidobacterium,
further enhancing NK cell functions and tumor regression. HSD decreases the expression of IL-17A and iNOS and inhibits inflammation, which
reduces enterotoxigenic Bacteroides fragilis (ETBF)-promoted colon carcinogenesis. HSD exacerbates Helicobacter pylori infection and promotes gastric
carcinogenesis. d High-fat diet (HFD), through augmentation of queuosine-producing gut bacteria, can incite chemotherapy resistance in pancreatic
cancer patients. HFD reduces SCFA-producing bacteria and SCFA production, leading to decreased levels of short-chain fatty acids (SCFAs) that
activate the MCP-1/CCR2 axis, which promotes M2 TAM recruitment and polarization, ultimately contributing to colorectal cancer (CRC) progression.
High bile salt hydrolase (BSH) enzyme activity in an HFD mouse model activates the β-catenin/CCL28 axis, further inducing immunosuppressive Tregs
and accelerating CRC progression. e Dietary intake rich in tryptophan stimulates certain Bacteroides to produce the metabolite indole-3-acetic acid (3-
IAA). Increased levels of 3-IAA enhance the efficacy of chemotherapy treatment. Dietary intake rich in tryptophan, through the action of the probiotic
Lactobacillus reuteri (Lr), leads to the production of the metabolite indole-3-aldehyde (I3A). This metabolite promotes the production of IFNγ from
CD8+ T cells, thereby enhancing antitumor immunity and the efficacy of immune checkpoint inhibitors (ICIs). f High-fiber diet enriches Akkermansia
muciniphila which produces the microbiota-derived STING agonist c-di-AMP, inducing type I interferon (IFN-I) production by intratumoural
monocytes, resulting in various TME modulation pathways, including reprogramming of mononuclear phagocytes into immunostimulatory
monocytes and DCs, promoting macrophage polarization toward an antitumor phenotype and stimulating crosstalk between NK cells and DCs,
further enhancing the therapeutic effect of immunotherapy. Dietary fiber inulin can enhance the effectiveness of anti-PD-1 therapy by increasing the
abundance of beneficial commensal microbes (e.g., Akkermansia, Lactobacillus and Roseburia) and SCFAs, further increasing the number of stem-like T-
cell factor-1 (Tcf1)+PD-1+CD8+ T cells numbers. Dietary fiber pectin can improve the effectiveness of anti-PD-1 therapy by increasing the abundance
of butyrate-producing bacteria, further promoting T-cell infiltration and activation in the TME. This figure was created with BioRender.com

Xiao et al.
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diet on chemotherapy effectiveness via gut microbiome adjust- IMPLICATIONS OF DIETARY INTERVENTION FOR OTHER
ments.307 Expanding on the theme of diet’s influence on DISEASES
chemotherapy effectiveness in pancreatic cancer, another study Dietary interventions may induce, prevent or delay the progres-
revealed that the microbiota-derived tryptophan metabolite sion of various diseases in addition to cancer, which also influence
indole-3-acetic acid (3-IAA) is enriched in patients responsive to human health and longevity. Healthy dietary patterns that are rich
chemotherapy. Through dietary manipulation of tryptophan, an in fiber and beneficial nutrients may reduce the risk of disease,
increase in 3-IAA production enhances chemotherapy efficacy by while unhealthy dietary patterns may increase the risk of disease
disrupting cancer cell metabolic fitness via increased reactive and worsen clinical outcomes.309 Here, we summarize preclinical
oxygen species and reduced autophagy.308 These findings further and human studies revealing the implications and mechanisms of
emphasize the crucial role of gut microbiota modulation via various dietary patterns on other diseases in addition to cancer,
dietary interventions in cancer treatment outcomes. including neurodegenerative diseases, autoimmune diseases,
Despite the significant progress in this field, the complex CVD, and metabolic disorders.
relationships among dietary factors, the gut microbiota, and
cancer treatment still need to be understood. Each individual’s Neurodegenerative diseases
microbiome is unique, influenced by genetics, diet, environment, Several neurodegenerative diseases (NDs), such as epilepsy,
and lifestyle, which adds layers of complexity to the task of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s
identifying universally beneficial interventions. Additionally, the disease (HD), and amyotrophic lateral sclerosis (ALS), which
development of high-throughput technologies and bioinformatics feature chronic progressive damage to the nervous system, have
tools for microbiome analysis will be vital in deciphering these been proven to be tightly connected with nutrient availability
complex interactions. These advancements could enable the and dietary patterns.310 The underlying mechanisms of various
identification of biomarkers for microbiome-related treatment dietary interventions mainly include altering neurotransmitters,
responses and the customization of diet-based interventions to remodeling, interfering with brain energy metabolism and
enhance the efficacy of cancer therapies. The identification of mitochondrial function, and altering inflammation and oxidative
specific dietary factors and gut microbiota constituents that can stress. The underlying mechanisms also include altering the
enhance the effectiveness of cancer therapies may lead to the composition and balance of the gut microbiome, which further
development of personalized treatments to improve therapeutic influence the process of neurodegeneration via the gut-brain
outcomes for cancer patients. axis (Fig. 4).
GABA
hippocampal catalase
Akkermansia gamma-glutamyl
GABA
Parabacteroides amino acids
KD
Bifidobacteria TNF
β-HB
β-HB
NLRP3 inflammasome activation
microglial activation
Firmicutes
Tenericutes
Opisthokonta
FMD Proteobacteria loss of dopaminergic neuron
propionic acid glial cells TNF-α and IL-1β
isobutyric acid
butyric acid
valeric acid TyrRS
tyrosine sirtuin pathway
amyloid-β protein
CR
BDNF, HSP70
NANA
naive CD4+ T cells
HFD CD4+ TEMs
Tregs
amyloid-β protein
MD phosphorylated tau
Fig. 4 Impact of different diets on neurodegenerative diseases. The ketogenic diet (KD) can enhance inhibitory neurotransmission and anti-
inflammatory effects in epilepsy, influence the gut microbiota, and elevate beneficial metabolites. KD is particularly beneficial for treating
pediatric drug-resistant epilepsy with elevated specific Bifidobacteria and TNF. In Alzheimer’s disease (AD) and Parkinson’s disease (PD), KD
could counteract decreased β-HB levels, inhibit the NLRP3 inflammasome, reduce pathology, and alleviate symptoms by inhibiting microglial
activation. Fasting mimicking diet (FMD) enhances the gut microbiota composition and metabolites, inhibiting neuroinflammation. This
results in the attenuated loss of dopaminergic neurons in the substantia nigra in patients with PD. Caloric restriction (CR) may prevent AD by
lowering serum tyrosine levels, reversing the exhaustion of tyrosyl-tRNA synthetase (TyrRS), and upregulating the sirtuin pathway, which
attenuates the amyloidogenic processing of amyloid-β protein precursor (APP). Dietary restriction can increase brain-derived neurotrophic
factor (BDNF) and chaperone heat-shock protein-70 (HSP70) levels in the striatum and cortex, which are relevant to Huntington’s disease (HD).
High-fat diet (HFD) can accelerate recognition-memory impairment in an AD mouse model by increasing blood N-acetylneuraminic acid
(NANA) levels, leading to systemic immune exhaustion. Conversely, the Mediterranean diet (MD) may protect against memory decline and
mediotemporal atrophy by lowering amyloid-β protein and phosphorylated tau levels, reducing AD risk. This figure was created with
BioRender.com

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KD has been clinically applied for nearly a century as alternative addition, high antigliadin antibody titers in patients with HD
therapy for childhood intractable epilepsy, but there is sufficient suggest the potential value of applying gluten-free diet in HD
evidence that a modified Atkins diet (MAD) is more tolerable and patients.343 A dietary restriction regimen retarded the progression
has a greater probability of causing seizure reduction than a of neuropathological, behavioral, and metabolic abnormalities in
classical KD according to a systematic review.311–313 Increased an HD model, resulting in an extension of life span by increasing
levels of the inhibitory neurotransmitter GABA can be observed in brain-derived neurotrophic factor and chaperone heat-shock
preclinical KD models and patient cerebrospinal fluid (CSF), protein-70 (HSP70) levels in the striatum and cortex, the
dampening neuronal excitability.314–316 An increase in peroxisome mechanisms of which still need further explanation.344 A cross-
proliferator activated receptor gamma 2 (PPARγ2) and upregula- sectional baseline analysis revealed that a higher intake of
tion of hippocampal catalase in KD-fed rats are observed, which antioxidants and carotenes may result in greater ALS function.345
may increase anti-inflammatory and antioxidant activity.317 In Another meta-analysis revealed that a greater intake of ω-3 PUFAs
addition, a KD may upregulate potassium channels that are is associated with a reduced risk of ALS.346 Although weight loss
sensitive to ATP opening, reducing the electrical excitability of the has been identified as a negative prognostic factor, high-calorie
brain and increasing the seizure threshold.318 The gut microbiota, fatty acid diet provides a significant survival benefit for patients in
which includes Akkermansia, Parabacteroides, and Bifidobacteria, the subgroup of fast-progressing ALS patients only.347
also contributes to the neuroprotective effects of KD on
epilepsy.319,320 Autoimmune diseases
Epidemiologic evidence indicates that obesity is an indepen- Different types of autoimmune diseases, including rheumatoid
dent risk factor for AD, while HFD is closely associated with an arthritis (RA), systemic lupus erythematosus (SLE), inflammatory
increased risk of obesity.321 Recognition-memory impairment in bowel disease (IBD), Hashimoto’s thyroiditis (HT), and multiple
an AD mouse model (5xFAD) can be accelerated by high-fat sclerosis (MS), can cause distinct clinical features from abnormal
obesogenic diet by increasing blood levels of the metabolite activation of the immune system that erroneously attacks healthy
N-acetylneuraminic acid (NANA), which results in systemic host cells and tissues. Impaired gut barrier function, also referred
immune exhaustion.322 HFD may also enhance neuroinflammation to as a “leaky gut”, which may disrupt the balance between
by increasing circulating free fatty acids and cytokines, which may tolerance and immunity to non-self-antigens, is often observed in
lead to cognitive impairment.323 Conversely, healthy dietary autoimmune diseases.348 This finding suggested a close relation-
interventions, including the Mediterranean diet (MD), CR, and ship between diet, the gut, and autoimmune diseases. Dietary
KD, may prevent AD progression.324–326 Adhering to MD may act interventions may influence the susceptibility, progression and
as a protective factor against memory decline and mediotemporal treatment response of these autoimmune diseases through
atrophy, as indicated by decreased levels of amyloid-β protein and various mechanisms, from adjusting inflammation levels and
phosphorylated tau, reducing the risk of AD.327 CR may prevent immune cell composition to adjusting the gut microbiome
AD by lowering serum tyrosine levels to reverse the exhaustion of composition (Fig. 5).
tyrosyl-tRNA synthetase (TyrRS) and upregulating the sirtuin A healthy MD may benefit RA by reducing inflammatory activity
pathway, which attenuates the amyloidogenic processing of and increasing physical function.349 Phenolic compounds in
amyloid-β protein precursor (APP), as confirmed by in vivo and extravirgin olive oil (EVOO), an essential component of the MD,
in vitro models.328,329 KD may reverse the decreased β-HB levels in can decrease joint edema, cell migration, cartilage degradation
red blood cells and the brain parenchyma of AD patients, hence and bone erosion by reducing the levels of proinflammatory
inhibiting NLRP3 inflammasome activation and reducing AD cytokines and prostaglandin E2 in the joint.350 However, the
pathology.330 In addition, diet can influence AD by modulating protective effect of high-fiber diet may be reversed if there exists
the gut microbiome and metabolites. For instance, a colonization of Prevotella copri, which leads to the overproduction
Mediterranean-ketogenic diet (MMKD) is associated with of organic acids, including fumarate and succinate, during the
improved AD biomarkers in CSF, as indicated by increased digestion of complex fibers and the promotion of proinflamma-
Akkermansia muciniphila levels, which modulate GABA levels and tory responses in macrophages, exacerbating arthritis in an RA
gut transit time.331,332 model.351 In addition, abundant supplementation of fish oil
Gut microenvironmental changes may trigger the development benefits the clinical outcome of RA by suppressing the production
of PD through the gut-brain axis, as determined by the presence of proinflammatory cytokines and cartilage degradative
of α-synuclein and Lewy bodies in the enteric nervous system and enzymes.352 The erythrocyte level of ω-6 PUFAs acts as a
the convincing association between PD and gut inflamma- biomarker that inverses the risk of RA, and the remission rate of
tion.333,334 Research has revealed changes in the gut microbiome RA increases when ω-3 PUFAs are added to disease-modifying
in PD patients compared to healthy volunteers, highlighting the anti-rheumatic drug (DMARD) treatment.353,354
potential benefits of dietary interventions in treating PD Dysbiosis of the gut microbiome can be observed in SLE
patients.335 High serum sodium is associated with cognitive patients, including a decreased richness and diversity of the gut
decline, as observed in the aged population.336 However, a recent microbiota and a reduced proportion of Firmicutes/Bacteroides (F/
study denies the association between HSD and neurodegenera- B); the latter may promote lymphocyte activation and Th17
tion or α-synuclein accumulation in a PLP-hαSyn model, suggest- differentiation from naïve CD4+ lymphocytes.355,356 Blooming of
ing that the mechanism of HSD needs further exploration.337 Ruminococcus (blautia) gnavus occurs at times of high disease
Adhering to MD is associated with a decreased incidence of PD, activity and during lupus nephritis, indicating that it is the driver of
the mechanisms of which may include reducing neuroinflamma- often remitting-relapsing SLE.357 Another analysis showed that
tion, similar to AD.338,339 KD ameliorates motor and nonmotor Veillonella dispar has a positive association with the activity of
symptoms in PD patients by inhibiting microglial activation340. SLE.358 According to a systematic review, nutritional support in the
FMD promotes a favorable gut microbiota composition and SLE population is focused mainly on interventions involving ω-3
metabolites and inhibits neuroinflammation, consequently attenu- and vitamin D.359 The anti-inflammatory effect of ω-3 may
ating the loss of dopaminergic neurons in the substantia nigra in a contribute to its clinical function, similar to that of RA.360 Vitamin
PD model.341 D blocks the proliferation, differentiation and function of B cells
Other neurodegenerative diseases with lower incidence rates and T cells, which may attenuate the expression of inflammatory
are also relevant to dietary interventions. A clinical trial suggested cytokines in patients with SLE.361 Inadequate levels of serum
that increased consumption of dairy products may increase the vitamin D have been observed in SLE patients, suggesting the
risk of phenoconversion, resulting in earlier onset of HD.342 In importance of supplementing their diet with vitamin D362. Dietary

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Prevotella copri
fumarate, succinate
proinflammatory B cells, T cells, DCs

response Tregs, NK cells
in macrophages
pro-inflammatory cytokines
IL-12, IL-1, IL-6, TNFα
cartilage degradative enzymes
IL-4, IL-5, IL-10
RA SLE
IL-1β
TGFβ signalling
TNFα
IL-6
PGE2 myelin-debris clearance
in microglia
IBD MS
Bifidobacterium adolescentis GM-CSF, TNFα, IL-2

Bifidobacterium longum
Faecalibacterium prausnitzii
Th17 cells
Enterobacteriaceae Th17 cells

Tregs
microbial diversity
epithelial mitochondrial function
+ antibiotics
Fig. 5 Impact of different diets on autoimmune diseases. Extravirgin olive oil (EVOO) can reduce joint inflammation and degradation in
rheumatoid arthritis (RA) due to its phenolic compounds. However, the protective effects of a high-fiber diet can be reversed by Prevotella
copri colonization, which promotes proinflammatory responses. Fish oil supplementation can suppress proinflammatory cytokines and
cartilage degradation, improving RA outcomes. Vitamin D can inhibit the proliferation, differentiation, and function of B and T cells,
potentially reducing inflammatory cytokine expression in systemic lupus erythematosus (SLE) patients. A diet low in fermentable
oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can alleviate gut symptoms in quiescent inflammatory bowel
disease (IBD) patients, possibly by regulating the immune response through reducing fecal microbial abundance. However, a high-fat diet
(HFD) can exacerbate pre-IBD inflammation by impairing epithelial mitochondrial bioenergetics and triggering microbiota disruptions,
especially when combined with antibiotics. High salt diet (HSD) can exacerbate autoimmune conditions such as multiple sclerosis (MS) by
promoting the induction of pathogenic Th17 cells. Intermittent fasting (IF) can improve MS by reducing the number of IL-17-producing T cells,
increasing the number of Tregs in the gut, and enhancing antioxidative microbial metabolic pathways. However, the Western diet can impair
myelin-debris clearance in microglia, hindering lesion recovery after demyelination and potentially contributing to MS induction. This figure
was created with BioRender.com
patterns other than single nutrients as supplementary treatments IBD treatment according to clinical guidelines.364 Obesity is a risk
for SLE still require further investigation.363 factor for IBD, especially for CD.365 As a potential trigger of obesity,
Ulcerative colitis (UC) and Crohn’s disease (CD) are the two HFD, together with antibiotics, exacerbates inflammation in pre-
major clinical phenotypes of IBD. Dietary management and IBDs by impairing epithelial mitochondrial bioenergetics and
microbiota modulation have been clinically recommended for triggering microbiota disruptions in mouse models.366 However,

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IBD increases the risk of malnutrition, which triggers inflammatory Therapeutic implications of diet for CVD treatment have also
responses and subsequently leads to poor clinical outcomes.367 been a focus of recent studies. CR attenuates hypertension, left
Therefore, dietary interventions and nutritional care should be ventricular remodeling and diastolic dysfunction in DS/obese rats
planned according to the precise nutritional assessment and by reducing cardiac oxidative stress and inflammation.389 In
dietary assessment for IBD patients.368 Exclusive enteral nutrition addition, a combination of CR and exercise can improve cardiac
(EEN), the first-line therapy in pediatric patients with active CD, mitochondrial dynamics, decrease cardiac apoptosis, and maintain
can effectively decrease clinical activity and reduce the complica- cardiac [Ca2+]i homeostasis in obese insulin-resistant rats.390 CR
tions of CD simultaneously, but its benefit in adults still lacks also helps to maintain the iron homeostasis of cardiomyocytes.391
competent evidence.369 Similarly, CD exclusion diet (CDED) These findings suggest the function of CR in cardiac protection.
positively correlates with the clinical remission of pediatric However, strictly adhering to CR is very difficult for most patients.
patients with active CD.370 In addition, diet low in fermentable IF is easier to perform than CR and has similar potential clinical
oligosaccharides, disaccharides, monosaccharides, and polyols value.392 FMD, a 5-day fasting dietary pattern, increases cardiac
(FODMAPs) can relieve the gut symptoms of patients with vascularity and function and resistance to cardiotoxins in a high-
quiescent IBD, possibly reducing the fecal abundance of microbes fat, high-calorie diet (HFCD) mouse model, thereby postponing
and thereby regulating the immune response of the host.371 the process of cardiac aging.393 Alternate day fasting (ADF)
Dietary interventions may also influence the risk and clinical improves cardiovascular marker levels, including reduced fat mass,
outcome of other autoimmune diseases. A recent study on HT an improved fat-to-lean ratio, and increased β-HB-hydroxybuty-
suggested that low intake of animal foods, mainly meat, has a rate levels, suggesting its clinical relevance for CVD interven-
protective effect on thyroid autoimmunity and potentially has a tion.394 KD has a beneficial effect on the blood lipid profile, the
positive influence on redox balance, which further reduces NLRP3 inflammasome, myocardial energy metabolism, and the
oxidative stress-related disorders.372 Improvement in HT has also vascular endothelium, benefiting CVD patients.395 However,
been observed in other dietary interventions, including elimina- research on healthy individuals has reported that lipid profiles
tion of gluten or lactose, energy restriction, and consumption of deteriorate in response to a KD, suggesting that its role in
Nigella sativa, suggesting the potential benefit of diet as a preventing CVD in the normal population needs further inquiry
complementary treatment for HT.373 MS is more common in (Fig. 6).396
western countries, suggesting diet as a potential risk factor.374
Western diet triggers impaired myelin-debris clearance in micro- Metabolic disorders
glia, thereby impairing lesion recovery after demyelination, which Overnutrition is a driving factor for obesity and related metabolic
may explain its role in MS induction.375 Moreover, an elevated disorders, mainly including type 2 diabetes mellitus (T2DM),
intake of dietary salt can exacerbate autoimmune conditions by metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and
promoting the induction of pathogenic Th17 cells, contributing to polycystic ovarian syndrome (PCOS).397 In addition, these meta-
MS.376 Conversely, IF diet ameliorates the clinical course and bolic disorders have a complicated internal relation, for instance,
pathology of MS by reducing the number of IL-17-producing T2DM and NAFLD are independent factors for each other, and
T cells, increasing the number of Tregs in the gut and increasing PCOS is closely related to insulin resistance and T2DM.398,399 These
the richness of gut bacteria, which enhance antioxidative epidemiological characteristics suggest a high correlation
microbial metabolic pathways.377 Vitamin D supplementation between dietary patterns and multiple metabolic disorders
has been shown to lower the incidence and benefit MS patients (Fig. 7). Changes in the gut microbiome may also explain the
with sufficient evidence, and a “Coimbra Protocol” referring to etiology of metabolic disorders by altering the levels of
daily doses up to 1000 I.U. vitamin D3 per kg body weight is metabolites, such as SCFAs and succinate.400
clinically applied to treat patients with MS.378,379 HFD is the standard method to induce obesity in animal models
and results from the overconsumption of fat, which directly
Cardiovascular diseases (CVD) increases caloric intake. The elevation of inflammatory mediators
According to epidemiological studies, obesity and unhealthy diet such as JNK and IκB kinase (IKK) in hypothalamic inflammation
are risk factors for CVD. Greater dietary fiber intake from cereal, may also explain the obesity induced by HFD.401 Interestingly, a
vegetables and fruits is associated with a lower risk of CVD, TRF with equivalent caloric intake from HFD has been shown to
suggesting that high-fiber diet is a potential protective factor.380 have a protective effect on HFD-induced obesity and associated
An experimental model fed with diet lack of prebiotic fiber complications by adjusting various signaling pathways and
induces hypertension through inducing deficiency of SCFA causing rhythmic creatine-mediated thermogenesis, which may
production and GPR43/109A signaling, suggesting the underlying further improve nutrient utilization and energy expenditure and
mechanisms of dietary fiber.381 Besides, high-fiber diet and reverse excessive daytime sleepiness induced by paraventricular
acetate supplementation can lead to changes in the gut thalamic nucleus (PVT) dysfunction.402–404 Adipose tissue hypoxia
microbiota, particularly an increase in Bacteroides acidifaciens, and inflammation may lead to adipocyte dysfunction and obesity-
which is protective against the development of CVD.382 Other induced insulin resistance in HFD-fed models, as indicated by
healthy dietary patterns, including the Nordic diet, the Dietary increased infiltration of adipose tissue macrophages (ATMs),
Approaches to Stop Hypertension (DASH) diet, the MD, and the activation of the NLRP3 inflammasome and increased levels of
vegetarian diet, also have protective effects on CVD risk.383 High proinflammatory cytokines.405–407 In addition to fat intake, the
sodium intake is the leading dietary risk factor for CVD.384 High overintake of fructose may also impair hepatic insulin sensitivity,
salt load may induce persistent hepatic steatosis and inflammation and several metabolic pathways are independent of increased
by inhibiting SIRT3 expression, thereby contributing to cardiovas- weight gain and caloric intake.408 Within this complex interplay of
cular damage.385 Conversely, a low-sodium diet may dampen the diet, metabolism, and inflammation, IL-17 has been identified as a
risk of CVD, which is highly recommended by current dietary key player in metabolic dysregulation associated with HFD, where
guidelines.386 Amino acids play different roles in the progression inhibiting IL-17A production or blocking its receptor can attenuate
of CVD. Diet with high-unsaturated fatty acid composition and less obesity by enhancing adipose tissue browning and energy
saturated fat might be cardioprotective.387 In contrast, higher dissipation.409 Complementarily, IL-17F promote the expression
intake of BCAAs is associated with increased platelet activity and of TGFβ1 in adipocytes, which fosters sympathetic innervation and
arterial thrombosis formation; therefore, BCAA levels are asso- suggests a novel therapeutic target for obesity that could
ciated with the risk of CVD.388 stimulate thermogenic activity in fat tissue, thereby improving

Xiao et al.
25
Calorie restriction Fasting/FMD Ketogenic diet

Toxic
blood lipid?
oxidative stress mitochondrial function
dynamics NLRP3
inflammation toxicity inflammasome
ion homeostasis fat mass
inflammation GPR34/109A thrombosis

signaling
hepatic steaosis
SIRT3 SCFA platelet activity
High-salt diet Low prebiotic diet High BCAAs diet

Fig. 6 Impact of different diets on cardiovascular diseases. Calorie restriction (CR) can reduce cardiac oxidative stress and inflammation,
improve cardiac mitochondrial dynamics and maintain cardiac ion homeostasis, which may be protective against cardiovascular disease (CVD)
in obese and/or insulin-resistant models. Fast-mimicking diet (FMD) increases cardiac vascularity and function and resistance to cardiotoxins
in a high-fat, high-calorie diet (HFCD) mouse model. Alternate day fasting (ADF) improves cardiovascular markers, for example, reduced fat
mass. Ketogenic diet (KD) inhibits the NLRP3 inflammasome and improves the blood lipid profile but may lead to impaired blood lipid profiles
in healthy individuals. High-salt diet (HSD) can inhibit SIRT3 expression and induce persistent hepatic steatosis and inflammation, thereby
contributing to cardiovascular damage. A diet lacking prebiotic fiber induces hypertension through inducing a deficiency in short-chain fatty
acid (SCFA) production and GPR43/109A signaling. High branched-chain amino acid (BCAA) intake is associated with increased platelet
activity and arterial thrombosis formation. This figure was created with BioRender.com
metabolic health and providing a potential treatment strategy for levels and reducing hepatic steatosis in patients with NAFLD,
obesity and its related metabolic disorders.410 possibly by downregulating hepatic inflammatory pathways,
Cohort studies have demonstrated that healthy diets, including modifying lipogenic gene expression and increasing levels of
the Portfolio diet, DASH diet, and MD, are associated with a autophagy.427,428
decreased risk of T2DM.411–413 The promotion of SCFA-producing PCOS features a series of metabolic irregularities, mainly
bacteria induced by dietary fibers observed in T2DM patients androgen excess and ovarian dysfunction. A meta-analysis
suggests the potential value of fiber supplementation in clinical showed that women with PCOS have a lower overall diet quality
practice.414 In addition, increased fiber consumption is associated with higher cholesterol, lower magnesium and lower zinc
with decreased insulin resistance, the mechanism of which mainly intake.429 Dietary modification with lower caloric intake to achieve
includes the gut microbiota and associated molecules.415,416 IF is weight loss is recommended as a first-line therapy for managing
an effective strategy for controlling weight and increasing insulin PCOS, and higher supplementary nutrient intake, including
sensitivity in patients with diabetes and can also improve vitamin D, chromium and ω-3, may also benefit patients suffering
cardiometabolic outcomes.417,418 The every-other-day fasting from PCOS.430 MD, KD and their combination can all lead to
(EODF) regimen selectively stimulates beige fat development significant improvements in body weight, metabolic function and
within white adipose tissue and shifts the gut microbiota ovulatory dysfunction in PCOS patients.431–433 In addition, IF may
composition in experimental models, explaining the mechanism be beneficial for treating anovulatory PCOS by reducing body fat
through which IF ameliorates obesity, insulin resistance, and and improving menstruation, hyperandrogenemia, insulin resis-
hepatic steatosis.419 KD has therapeutic effects on glycemia, lipid tance and chronic inflammation.434 CR may also improve weight
control, and weight reduction in T2DM patients.420 However, KD and metabolic disorders in patients with PCOS, alone or in
may contribute to decreased sensitivity to peripheral insulin and combination with supplementation.435 However, the exact
impaired glucose tolerance by upregulating insulin receptors, as mechanisms of these dietary interventions remain unclear and
determined by previous studies, which contradicts clinical need further exploration.
findings.421 While the potential of dietary interventions to influence
NAFLD features hepatic steatosis or adiposity with a potential systemic diseases of the whole body is supported by various
risk of developing into inflammation, fibrosis, and cancer. MD, as studies, a critical outlook reveals the necessity for more rigorous,
the most recommended dietary pattern for NAFLD, can reduce long-term clinical trials to validate these findings. It is essential to
liver steatosis and improve insulin sensitivity even without weight approach these interventions with caution, considering individual
loss in an insulin-resistant population.422 Reduced liver fat may be differences and the intricate balance of potential benefits against
associated with ameliorated inflammation induced by antiox- nutritional deficiencies or other risks.
idants, low glycemic response induced by dietary fiber, and
improved hepatic lipid metabolism.423 KD is more clinically
meaningful for glycemic control in individuals with T2DM and CONCLUSIONS AND PERSPECTIVES
NAFLD than low-calorie diet or high-carbohydrate, low-fat (HCLF) Our review provides compelling evidence that dietary interven-
diet.424,425 Mechanistically, ketone bodies may modulate inflam- tions, including calorie restriction, fasting or FMD, KD, protein
mation and fibrosis in hepatic cells.426 IF alone or combined with restriction diet, HSD, HFD, and high-fiber diet, have substantial
exercise is effective at lowering intrahepatic triglyceride (IHTG) potential for modulating metabolism, redirecting disease

Xiao et al.
26
High
diet -fib
h-fat er d
iet
Hig
Calorie intake
Ev
ng
JNK, IKK
er
di
y-
inflammation
fee
ot
he
ted
adipose hypoxia SCFA-producing
r-d
&inflammation bacteria
tric
ay
res
adjusted rhythmic
fast
creatine-mediated beige fat
Time
thermogenesis
ing
Obesity T2DM
PVT dysfunction gut microbiota
alteration
daytime sleepiness
glucose tolerance
Fructose ov
Insulin insulin receptor

Resistance
HOC
H2
hepatic insulin glycemia

sensitivity PCOS NAFLD
O
weight
O
H
HO
blood lipid
er-in
OH
et
CH2
c di
OH
take
inflammation
eni
metabolic function hepatic fibrosis
tog
ovulatory dysfunction
Ke
weight IHTG
hepatic steaosis
Ca
lo
lipogenic gene
ie
r
re autophagy
st
ric
tio
n
ise
exerc
Intermittent-fasting&
Fig. 7 Impact of different diets on metabolic disorders. High-fat diet (HFD) can directly increase caloric intake, induce inflammatory mediators
such as JNK and IκB kinase (IKK) to promote hypothalamic inflammation, and contribute to adipose tissue hypoxia and inflammation, which all
lead to the development of obesity and/or insulin resistance. Over-intake of fructose can also increase caloric intake and induce obesity by
impairing hepatic insulin sensitivity. However, time-restricted feeding (TRF) with equivalent caloric intake from HFD can adjust various
signaling pathways and rhythmic creatine-mediated thermogenesis and reverse excessive daytime sleepiness induced by paraventricular
thalamic nucleus (PVT) dysfunction, resulting in a protective effect on HFD-induced obesity. High-fiber diet can reduce inflammation and
insulin resistance by influencing the gut microbiota and associated molecules, for instance, SCFA-producing bacteria. Every-other-day fasting
(EODF) regimen can also shift the gut microbiota composition and stimulate beige fat development within white adipose tissue to inhibit
insulin resistance. Ketogenic diet (KD) is clinically beneficial for the glycemic control of type 2 diabetes mellitus (T2DM) and nonalcoholic fatty
liver disease (NAFLD). However, in experimental models, KD can decrease sensitivity to peripheral insulin by upregulating insulin receptors.
Intermittent fasting (IF) alone or combined with exercise can reduce intrahepatic triglyceride (IHTG) levels and hepatic steatosis in NAFLD
patients by downregulating hepatic inflammatory pathways, modifying lipogenic gene expression and inducing autophagy. Calorie restriction
(CR) can be effective at reducing weight loss and reversing ovulatory/metabolic dysfunction in polycystic ovarian syndrome (PCOS) patients.
This figure was created with BioRender.com
progression, and enhancing therapeutic responses. These findings Despite compelling evidence, the potential impact of dietary
highlight the pivotal role of diet, an important environmental interventions on disease treatment, particularly cancer treatment,
factor, in influencing tumor metabolism and the course of various is not fully understood.436 The latest American Society of Clinical
diseases, such as cancer, neurodegenerative diseases, autoim- Oncology (ASCO) guidelines suggest that “there is currently
mune diseases, CVD, and metabolic disorders. insufficient evidence to recommend for or against dietary

Xiao et al.
27
interventions such as ketogenic or low-carbohydrate diets, low-fat publish, or preparation of the manuscript. The figures were created with
diets, functional foods, or fasting to improve outcomes related to Biorender.com.
quality of life (QoL), treatment toxicity, or cancer control”.437 The
intricate relationship between dietary interventions and treatment
outcomes can be influenced by numerous factors, such as overall AUTHOR CONTRIBUTIONS
lifestyle habits, health status, specific disease type and its Y.-Z.J., Z.-M.S., Y.-L.X., and Y.G. designed and finalized the study. Y.-L.X., Y.G., and Y.-
corresponding treatment, degree of dietary alterations, and J.Q. wrote and edited the paper and generated the figures. All authors have read and
approved the article.
patient adherence. A comprehensive assessment of these
variables is crucial for understanding the precise impact of diet
on treatment efficacy.438,439 ADDITIONAL INFORMATION
With the recognition of metabolic reprogramming inherent in Competing interests: The authors declare no competing interests.
disease progression, particularly in malignancies, it is becoming
essential to explore the value of implementing dietary interven- Consent for publication: The content of this manuscript has not been previously
tions and translating the evidence into practice. Future research published and is not under consideration for publication elsewhere. All authors are
should focus on unraveling the specific molecular mechanisms aware of and agree to the content of the paper and are listed as coauthors of
involved, which will enable the development of more effective, the paper.
personalized dietary interventions that serve as adjunct therapies
in comprehensive disease management.
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Effects of Dietary Intervention On Human Diseases

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Effects of dietary intervention on human diseases: molecular

Signal Transduction and Targeted Therapy (2024)9:59 ; https://doi.org/10.1038/s41392-024-01771-x

INTRODUCTION adherence to the plant-based Paleolithic diet and a Paleolithic-like

Received: 1 August 2023 Revised: 5 February 2024 Accepted: 18 February 2024

© The Author(s) 2024

Signal Transduction and Targeted Therapy (2024)9:59

Naïve T cells M2-like macrophages

Glycolysis and PPP

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Dietary intervention Cancer type Results References

CD103+CD4+ cells↑, CD103+CD8+ cells↑

restriction L-cystathionine (LCYH)↓, SAM↓, 5’-methylthioadenosine (MTA)↓,

PD-1+ NK cells↓, CTLA-4↓, PD-1↓

TNFα↑, tumor growth↑

Signal Transduction and Targeted Therapy (2024)9:59

gastric inﬂammation and gastric macrophage colony-stimulating factor↑, phosphorylated STAT3↑

CD4+ T cells↓, CD8+ T cells↓, central memory CD4+ T cell↓, effector

PMN-MDSCs↑, Arg1+ MDSCs↑, the expression of Arg1 and S100a9↑

Signal Transduction and Targeted Therapy (2024)9:59

(vs. olive oil high-fat diet) T cells↓

Colorectal cancer DCs↑, monocytes↑

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Signal Transduction and Targeted Therapy (2024)9:59

Signal Transduction and Targeted Therapy (2024)9:59

Dietary intervention Cancer type Comparison of Results References

Melanoma HO-1↓, Tregs↓

protein/80% methionine- like ratio↑, CD8+ T cells/M-MDSC ratio↑, CD8+ T cells/PMN-

restriction Colorectal cancer Radiotherapy Alterations in one-carbon metabolism 264

Soft-tissue sarcoma Antimetabolite

Signal Transduction and Targeted Therapy (2024)9:59

T cells↑, Tcf1+PD-1+CD8+ T cells↑, neutrophils↑, M1/M2

Due to their expression of oncogenes, cancer cells are more Radiotherapy

Signal Transduction and Targeted Therapy (2024)9:59

Dietary intervention NCT Therapeutic intervention Disease Status

Signal Transduction and Targeted Therapy (2024)9:59

NCT05708352 Chemotherapy and/or radiotherapy Glioblastoma Recruiting

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Signal Transduction and Targeted Therapy (2024)9:59

Signal Transduction and Targeted Therapy (2024)9:59

Bifidobacterium bifidum DCs

IL-17A& iNOS SCFAs Bacteroides

Helicobacter pylori queuosine-producing β-catenin/CCL28 MCP-1/CCR2

Signal Transduction and Targeted Therapy (2024)9:59

Signal Transduction and Targeted Therapy (2024)9:59

Signal Transduction and Targeted Therapy (2024)9:59

proinflammatory B cells, T cells, DCs

Bifidobacterium adolescentis GM-CSF, TNFα, IL-2

Enterobacteriaceae Th17 cells

epithelial mitochondrial function

Signal Transduction and Targeted Therapy (2024)9:59

Signal Transduction and Targeted Therapy (2024)9:59

Calorie restriction Fasting/FMD Ketogenic diet