Exosome-Mediated Metabolic Reprogramming: The Emerging Role in Tumor Microenvironment Remodeling and Its in Uence On Cancer Progression

Signal Transduction and Targeted Therapy www.nature.
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REVIEW ARTICLE OPEN
Exosome-mediated metabolic reprogramming: the emerging

role in tumor microenvironment remodeling and its influence
on cancer progression
Enli Yang1,2, Xuan Wang1,2, Zhiyuan Gong1,2, Miao Yu1,2, Haiwei Wu1,2 and Dongsheng Zhang1,2
Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing
cancer cells adapt to their increasing energy demands. Recently, extracellular vesicles (EVs) known as exosomes have been
recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Meanwhile, the TME is a highly
heterogeneous ecosystem incorporating cancer cells, fibroblasts, adipocytes, endothelial cells, mesenchymal stem cells, and
extracellular matrix. Accumulated evidence indicates that exosomes may transfer biologically functional molecules to the recipient
cells, which facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the
metabolism of cancer cells and their surrounding stromal cells. In this review, we present the role of exosomes in the TME and the
underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming. In addition, we will
also discuss the potential role of exosomes targeting metabolic process as biomarkers for tumor diagnosis and prognosis, and
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exosomes-mediated metabolic reprogramming as potential targets for cancer therapy. Furthermore, a better understanding of the
link between exosomes and metabolic reprogramming, and their impact on cancer progression, would provide novel insights for
cancer prevention and treatment in the future.
Signal Transduction and Targeted Therapy (2020)5:242 ; https://doi.org/10.1038/s41392-020-00359-5
INTRODUCTION other biologically active constituents. The role of exosomes in

In the past decade, the cancer metabolism has received enormous intercellular communication is accomplished by mediating the
interest and wide attention. A common metabolic feature of exchange of substances between cells, thereby changing the
cancer cells is obtaining necessary nutrient from a nutrient- biological properties of the recipient cells. Therefore, exosomes
deficient environment and using the nutrient to maintain cell have emerged as essential players in extracellular communica-
viability, proliferation, and build biomass. The metabolic activity of tion.5,6 Accumulated evidence indicates that cancer cells actively
cancer cells is altered compared with normal cells, and these release exosomes into the surrounding microenvironment, and
changes support the acquisition and preservation of malignant these vesicles have the pleiotropic capacity in regulating tumor
features. Therefore, metabolic reprogramming is regarded as one growth and progression, neovascularization, immune escape,
of the hallmarks of cancer.1,2 The abnormal metabolic functions of promoting tumor invasion, and metastasis.7,8 Therefore, exosomes
cancer cells were first proposed by Otto Warburg, who discovered could regulate intercellular communication not only between
that cancer cells consumed more glucose relative to normal cells. cancer cells, but also with the TME.9 Up to now, most researches
Besides, the rate of glycolysis in cancer cells is much higher than focus on exosomes containing certain proteins and RNAs. Never-
oxidative phosphorylation (OXPHOS), even under sufficient oxy- theless, recent researches have shown that the components
gen conditions; this phenomenon is known as the Warburg of exosomal cargo are far more complicated and contain
effect.3 Since then, a number of researches have focused on the metabolites. These molecular metabolites could be transferred
cancer-related metabolic reprogramming in the metabolic path- to surrounding cancer cells via exosomal pathway and
way, including metabolic changes in glucose, amino acids, and influence the metabolism of recipient cells to favor cancer
lipids, to explore potential therapeutic targets in cancer progression.10,11
progression. There is a growing body of studies that describe a relationship
Exosomes are membrane-coated vesicles, which are a subset of between exosomes and the tumor development and summarize
EVs with a 40–100-nm diameter. Exosomes are secreted by many the regulatory effects of exosomes on cancer therapy resistance,
kinds of cells into the extracellular microenvironment through the metastasis, and immunity.12–14 On basis of these studies, we
multivesicular bodies (MVBs), including cancer cells.4 Exosomes particularly focus on the emerging role of exosome-mediated
contain protein, mRNA, miRNA, transcription factors, lipids, and metabolic reprogramming in the regulation of the TME and cancer
1
Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, 250021 Jinan, China and
2
Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, 250021 Jinan, China
Correspondence: Haiwei Wu (hwwu@sdfmu.edu.cn) or Dongsheng Zhang (ds63zhang@sdu.edu.cn)
These authors contributed equally: Enli Yang, Xuan Wang
Received: 5 August 2020 Revised: 11 September 2020 Accepted: 27 September 2020
© The Author(s) 2020

Exosome-mediated metabolic reprogramming: the emerging role in tumor. . .
Yang et al.
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progression in the present review, which can provide potential established for exosome isolation, differential ultracentrifugation
anti-cancer therapeutic targets in the future research. has been proved to be effective in different studies.25 The
detection of exosomes can be achieved by nanoparticle tracking
analysis (NTA) and transmission electron microscopy (TEM);
EXOSOME AND METABOLIC REPROGRAMMING additionally, western blotting can be applied to analyze exosomal
Biogenesis and characteristics of exosome markers. The exosomal markers include ESCRT-related proteins
The formation of exosomes is a tightly regulated process and (Tsg101 and Alix), tetraspanins (CD81, CD63, and CD9), cytoplas-
undergoes four main processes (Fig. 1): initiation, endocytosis, mic proteins (Hsp90 and Hsp70), Integrins, and Annexins.
MVBs formation, and secretion of exosomes.15
The cell membrane sags inward to form the early endosomes, The metabolic reprogramming in cancer cell
with accumulating intraluminal vesicles (ILV) in their lumen. Then, During cancer progression, cancer cells should exhibit high
early endosomes maturation lead to MVBs formation. Generally, metabolic plasticity to adapt themselves to the dynamic changes
the MVBs are degraded by fusing with the lysosome, but some in tumor.26 High oxygen and nutrient utilization rate is essential to
MVBs are combined with plasma membrane and secreted maintain heightened biosynthetic and bioenergetic demands for
exosomes to extracellular space.16 To date, the most exhaustive tumor cell proliferation and dissemination.26 Normally, cells mainly
mechanism that described the generation of ILVs and MVBs are utilize glucose to generate ATP. Metabolism of glucose is mainly
the ESCRT-independent or -dependent pathways.17 Rab guanine accomplished by glycolysis or tricarboxylic acid (TCA) cycle-
triphosphatase, also known as GTPase, has been considered as a mediated OXPHOS. Glycolysis produces less ATP per mole glucose
vital regulatory mediator in the secretion of exosomes. Besides, compared to OXPHOS. In other words, glycolysis produces 2 moles
the results from Ostrowski et al.18 demonstrated that Rab27a and ATP per mole of glucose, while OXPHOS produces 36 moles ATP
Rab27b promoted the occurrence and stability of MVBs docking. per mole of glucose.27 Normal cells prefer to use glucose to
Another study showed that KIBRA could regulate exosome generate pyruvate, and then utilize TCA and OXPHOS to produce
secretion by inhibiting proteasome degradation of Rab27a, and ATP. On the contrary, cancer cells prefer to use glycolysis rather
KIBRA depletion could increase the number and size of MVBs.19 than OXPHOS under normoxia conditions to create energy. The
Furthermore, HSP90 and mTORC1 were also reported to have a increased glucose uptake and the enhanced glycolysis, as well as
regulatory effect on exosomal secretion.20,21 high production of lactate even under the aerobic condition, are
Exosomes are nano-sized extracellular vesicles, also referred to considered as a hallmark of the tumor. These changes in
as “cargo”, which consist of a bilipid layers. Exosomes encapsulate metabolism are called “Warburg effect”. With the favor of tumor
a large number of molecules, including proteins, nucleic acids, Warburg effect, energy can be rapidly produced and conducive to
lipids, and metabolites. This exosomal cargo is highly variable, other metabolic pathways to produce lipids, amino acids and
depending on the source of cell types, the state of the cell, and its nucleotides for cancer cell growth.28
microenvironment.17,19 Exosomes can transfer the information to In addition to glucose, lipids, and amino acids are also
recipient cells in three different pathways: (1) The protein on the important metabolites for tumor cell growth and progression.
exosomal membrane directly contacts the protein on the receptor Lipid metabolism is also changed in highly proliferating cancer
cell membrane, and then triggers the intracellular signaling cells that have an increased demand for cholesterol and lipids.
cascade; (2) the exosomal membrane fuses with the recipient Carbon should be transferred from energy generation to fatty
cells membrane and releases its contents into the recipient cell; (3) acids (FAs) for signaling lipids, membrane biosynthesis, or energy
targeting cells directly phagocytose exosomes and internalize sources. In order to meet their needs, cancer cells will uptake
them into their components.22 exogenous lipoproteins and lipids to enhance de novo synthesis
Different approaches have been developed for the isolation and of FAs and cholesterol biosynthesis.29 FAs synthesis occurs mainly
purification of exosomes based on their biological, physical, and in the cytoplasm. Firstly, acetyl-CoA is converted to malonyl-CoA
chemical properties, including ultracentrifugation, ultrafiltration, by acetyl-CoA carboxylase (ACC). Then, fatty acid synthase (FASN)
size exclusion chromatography, and microplate-based magneto- assembles malonyl-coenzyme A to palmitate. At present, the
immunocapture.23,24 At present, the most widely accepted expression of three key enzymes related to FAs synthesis,
technique for exosome isolation is the differential ultracentrifuga- including FASN, ACC, and ATP-citrate lyase (ACLY), have been
tion. Although no uniform identification criteria have been upregulated in various types of tumors. Inhibition of these
enzymes can suppress tumor growth both in vivo and
in vitro.30,31 Moreover, FA oxidation (FAO) has emerged as critical
players in the cancer cells metabolism, and the upregulated FAO
facilitates the proliferation and survival of cancer cells.32 Mean-
while, NADPH produced by FAO can make cancer cells counteract
oxidative stress.33 Another frequent metabolic change in cancer
cells is increased amino acid metabolism, especially glutamine and
serine metabolism. Glutamine is a major energy substrate, and the
metabolism of glutamine could produce α-ketoglutarate and TCA
cycle intermediates to provide an additional energy source for
cancer cells.34 Glutamine metabolism is influenced by multiple
oncogenic signaling pathways. For example, overexpressing MYC
by tumors shows a dependence on glutamine metabolism, and
MYC can promote the expression of glutamine transporters and
glutaminase (GLS).35 Serine biosynthesis has also been investi-
Fig. 1 The biogenesis and characteristics of exosomes. Exosomes gated in cancer cells. Phosphoglycerate dehydrogenase (PHGDH)
are secreted by donor cells into the intercellular microenvironment is a crucial enzyme for serine synthesis, and the expression levels
through the multivesicular bodies (MVBs). Exosomes can transfer
biologically functional molecules to recipient cells through three of PHGDH are significantly increased in breast cancer cells.36
ways, including a intercellular signaling through receptor-ligand With the in-depth study of tumor metabolism, the realization of
binding, b exosomes directly fuse with the recipient cells membrane metabolic reprogramming in the cancer has gone far beyond
and release their contents, and c recipient cells phagocytose originally described “Warburg effect”. A better understanding of
exosomes tumor metabolic alterations and its underlying molecular
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Fig. 2 The exosome-mediated metabolic reprogramming in the tumor microenvironment. Exosome-mediated metabolic reprogramming
occurs in cancer cells and their surrounding stromal cells in the TME. Stromal cells metabolic reprogramming is affected by exosomes derived
from cancer cells, and acts as a feedback loop to drive metabolic changes in cancer cells or to provide metabolic resources required for cancer
progression
mechanisms will help us explore more effective cancer treatment. growth and progression through various pathways, such as
Moreover, selectively targeting the metabolic reprogramming of secretion of inflammatory factors and growth factors.42
tumor cells will be an attractive direction for cancer treatment. Recent studies showed that CAFs play a vital role in tumor
growth through regulating metabolism. Cancer cells can promote
glycolysis of CAFs. In turn, CAFs can provide metabolites for cancer
EXOSOME-MEDIATED METABOLIC REPROGRAMMING IN THE cells and facilitate cancer cells proliferation through the TCA cycle
TME and OXPHOS. This phenomenon was recognized as the “Reverse
Exosomes have been considered as critical mediators in cancer Warburg Effect”.43 Recently, the export of lactate in CAFs and the
progression, where they regulate extracellular communication not uptake of lactate in cancer cells has been confirmed in the
only with the cancer cells but also with the stromal cells.22 The metabolism of cancer.44 The lactate symporters MCT1 and MCT4
TME is a highly complex and heterogeneous ecosystem incorpor- are critical regulators in establishing a lactate shuttle system.
ating cancer cells, fibroblasts, adipocytes, endothelial cells, MCT4 favors export of lactate, whereas MCT1 facilitates cellular
mesenchymal stem cells, and extracellular matrix (Fig. 2). It has lactate uptake. Thus, the tumor that utilizes the “Reverse Warburg
been widely accepted that the development of TME is crucial for Effect” is featured by higher MCT4 expression in CAFs and higher
cancer progression.37 Exosome-mediated metabolic reprogram- MCT1 expression in tumor cells.44 Additionally, more recent
ming is not limited to cancer cells, but is also found in stromal cells studies indicated that Caveolin-1 (Cav-1) might contribute to
in the TME, which suggested the involvement of exosome- cancer progression by regulating the metabolism of CAFs.45,46
mediated metabolic reprogramming in the TME. The metabolic Cav-1 is a membrane-bound scaffolding protein related to
remodeling in stromal cells is influenced by the cancer cells and endocytosis, signaling transduction, cell migration, and the
acts as a feedback loop to facilitate the growth of cancer cells.38 distribution of cholesterol.45 The reactive oxygen species (ROS)
Stromal cells could drive the metabolic changes in the cancer cells that is secreted by the cancer cells induces oxidative stress in
and provide the metabolic resources needed for cancer CAFs, which leads to autophagy and causes the degradation of
progression.38 Cav-1 and mitochondria.47,48 Moreover, Michael and colleagues49
found that knockdown of Cav-1 resulted in significant upregula-
Cancer-associated fibroblast tion of glycolytic enzymes, including lactate dehydrogenase and
Cancer-associated fibroblasts (CAFs), as the major component in pyruvate kinase. These results further demonstrate that the
the TME, are mostly defined by morphological features or metabolic symbiosis exists between cancer cells and CAFs.
expression of markers, including α-smooth muscle actin (αSMA), In recent years, there is growing evidence that exosomes have
fibroblast-specific protein-1 (FSP1/S100A4), and fibroblast activa- been recognized as crucial mediators in regulating the extra-
tion protein (FAP).39 Normal fibroblasts could be activated during cellular communication and metabolic reprogramming between
wound healing and inflammation, and these activated fibroblasts CAFs and cancer cells. Several studies have shown that cancer
are usually termed as myofibroblasts.40 Similarly, the cancer cells were capable of transforming normal fibroblasts to CAFs
development might be considered as a “cancer wound”, which through exosomes.50,51 Webber et al.50 indicated that exosomes
could activate the fibroblasts into CAFs.41 CAFs are derived from secreted by prostate cancer cells contained TGF-β and could
different origins, mostly from normal fibroblasts, epithelial cells, mediate the activation of fibroblasts. Besides, another study noted
mesenchymal cells, endothelial cells, epithelial-mesenchymal that different pathological stage of colorectal cancer-derived
transition (EMT) and endothelial to mesenchymal transition exosomes could lead to different stages of CAF-like changes in
(EndMT).42 Furthermore, CAFs are considered to promote tumor normal fibroblasts and increased expression of CAF marker α-

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SMA.51 Meanwhile, exosome-activated fibroblasts showed signifi- progression. The neovascularization supplies nutrient and oxygen
cant downregulation of Cav-1 and upregulation of the glucose to cancer cells, which support tumor progression and provide
transporter GLUT1. Increased expression of GLUT1 enhanced the pathways for tumor metastasis.69 The sustained hypoxia, com-
uptake of glucose and promoted the glycolysis in the activated bined with the secretion of cytokines, such as VEGF, facilitates
fibroblasts.51 Furthermore, the vital role of cancer cells-released tumor revascularization by triggering the remodeling of endothe-
exosomes in remodeling fibroblasts metabolism and promoting lial progenitor cells that are derived from bone marrow toward
glycolysis were also confirmed in breast cancer cells.52,53 cancer.70
Additionally, exosomes derived from cancer cells could induce Glycolysis is a hallmark of tumor ECs, and the ECs in the tumor
the expression of MCT4 in CAFs to export β-HB and lactate into vasculature depend more on glycolysis to produce ATP than
the cancer cells, and cancer cells expressing MCT1 utilize lactate to normal ECs.71 A hyperglycolytic phenotype was confirmed in
improve the level of OXPHOS.53,54 All these results demonstrated tumor ECs, which is evidenced by the enhanced expression of the
that exosome-mediated metabolic reprogramming plays a crucial glycolytic key enzyme PFKFB3 and the glucose transporter
role in the intercellular communication between cancer cells GLUT1.71
and CAFs. Recently, research shows that exosomes secreted by cancer
cells can remodel the metabolism of ECs. Wang et al.72 found that
Cancer-associated adipocyte exosomes derived from acute myeloid leukemia (AML) cells,
Considering the link between cancer progression and obesity, containing VEGF/VEGFR, could promote the glycolysis in ECs.
adipocytes are identified as an essential component of the TME.55 Although recent studies have discovered the potential role of
Dirat et al.56 reported that adipocyte co-cultivated with cancer exosomes secreted by cancer cells on regulating the metabolism
cells exhibited a changed phenotype with reduced lipids content of ECs, few studies have focused on the feedback effects of ECs-
and decreased adipocytes markers. Overexpression of IL6, IL1, and derived exosomes on cancer cells in the tumor field. However, a
MMP11 were also detected in the activated adipocytes, which are research has shown that lower levels of ECs-derived microvesicles
referred to as cancer-associated adipocytes (CAAs).56 Then, CAAs are related to better survival after chemotherapy in breast cancer
proceed to cultivate with cancer cells and adopt a phenotypical patients, suggesting that ECs-derived exosomes also might have
change to generate fibroblast-like cells named adipocyte-derived an important influence on tumor progression.73
fibroblasts (ADF), which may be part of the CAFs population in the
desmoplastic reaction of cancer.57 CAAs play functional roles in Mesenchymal stem cell
the tumor aggressiveness and progression through endocrine and Mesenchymal stem cells (MSCs) are pluripotent cells, which can
paracrine influences on cancer cells by secreting adipocyte- differentiate into multiple mesenchymal lineages, including
derived factors, such as leptin, adiponectin, resistin, visfatin, TNF-α, mesenchymal stromal cells and multipotent stem stromal cells.
IL-6, and MCP-1.58,59 Conversely, Cancer cells-derived signaling The multi-lineage differentiation of MSCs determines its profound
molecules triggered the lipolysis in CAAs and led to adipose effects on the function and formation of TME.74 MSCs presented in
atrophy in the human body, which is a manifestation of the cancer tissue throughout the body, such as bone marrow, ovary, and
cachexia.58,60 omentum, which is advantageous for wound healing and tissue
Lately, adipocytes were mainly considered to be great energy repair.75 In the TME, tumor-secreted factors induce tumor-
storage and provided high-energy metabolites in the TME.61 For promoting phenotypes in MSCs population, developing cancer-
example, CAAs released exogenous FFAs, which were taken up by associated mesenchymal stem cells (CA-MSCs).76 CA-MSCs can
cancer cells via cell surface CD36.62 Additionally, FFAs could differentiate into crucial stromal components, including CAFs and
provide sufficient energy for cancer cells through FAO.63 Thus, CAAs. Compared with normal tissues MSCs, CA-MSCs exhibited a
CAAs can regulate the metabolic reprogramming of cancer cells, high expression of TGF-β superfamily member, which is essential
which in turn promote cancer progression. for cancer progression, tumor proliferation, and induction of
Numerous studies have shown that exosomes mediate impor- chemoresistance.75,76
tant communication between CAAs and cancer cells. Some Little is known about the role of metabolic changes on the
previous studies have indicated that breast cancer cells-derived intercellular communication between MSCs and cancer cells in
exosomes could remodel the resident adipocytes tending to tumor progression. However, MSCs have the ability to differentiate
activated phenotype by promoting beige/brown differentiation into CAFs which influence the growth and invasion of cancer cells
and increasing the catabolism in adipocytes.64,65 Meanwhile, MSC- by secreting diverse metabolites, cytokines, and growth factors.77
differentiated adipocytes-associated exosomes could be incorpo- In fact, the metabolic crosstalk between cancer cells and CAFs
rated by breast cancer cells, which promoted the proliferation and deeply affects TME remodeling, which critically drives tumor
migration of cancer cells.66 A study by Lazar et al.67 revealed that growth.78
exosomes secreted from adipocytes were internalized by mela- Cancer cells can affect the metabolic reprogramming of CA-
noma cells, which consequently promoted the tumor invasion and MSCs through secreted factor-mediated intercellular communica-
migration. Meanwhile, the proteome of exosomes showed an tion. Furthermore, exosomes play an important role in this regard.
enrichment in proteins associated with lipid metabolism (e.g., Ma et al.79 showed that glioma cells-derived exosomes remodeled
FAO-catalyzing enzymes), which significantly enhanced FAO in glucose metabolism and promoted the glycolysis in MSCs, leading
melanoma cells.67 Similarly, another study also found that to their transformation of the tumor-like phenotype. Moreover,
enriched FAO-related proteins were harbored in EVs from Dai et al.80 showed that exosomes secreted by prostate cancer
adipocytes, and melanoma cells could uptake these exosomes containing PKM2 were transferred to MSCs, which could promote
to fuel FAO. Intriguingly, adipocyte EVs-induced FAO is enhanced the progression of tumor metastasis. Additionally, MSCs influ-
by obesity, but the process does not dependent on increased enced by cancer-exosomes could secret more exosomes as a
protein transfer.68 Consequently, it could be speculated that feedback, which could promote tumor angiogenesis by up-
adipocytes-originated exosomes might exacerbate tumor devel- regulating the level of glycolysis.81
opment by remodeling cancer cells metabolism.
Tumor-associated macrophage
Endothelial cell Macrophages are vital drivers of pro-tumor inflammation. Macro-
The cancer-associated endothelial cells (CAECs) are important phages could be polarized to M1 type after stimulating by IL-12,
components in the TME. It is widely accepted that CAECs- IFN-γ, LPS, TNF-α, Toll-like receptor (TLR) agents, and have a crucial
mediated tumor angiogenesis is of vital importance for tumor role in mediating helper T cell 1 (Th1) type immune response and

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anti-pathogen infection. IL-4, IL-5, IL-10, IL-13, CSF1, TGF-β1, and
prostaglandin E2 (PGE2) induce macrophages to M2 type
polarization that has been concerned as an important mediator
in the process of tissue repairing and wound healing.82,83
Tumor-associated macrophages (TAMs) are one of the major
immune cells in the TME. TAMs counteract the cytotoxic effects of
NK cells and T cells, thereby facilitating the escape of cancer cells
from immune surveillance, which plays a crucial role in cancer
proliferation and migration.38 TAMs are highly plastic, with M1
type TAMs exhibiting immunostimulatory properties and M2 type
TAMs exhibiting immunosuppressive properties.84 TAMs in tumor
usually exhibit an M2 phenotype, which is usually related to poor
prognosis.85 Abundant studies have demonstrated that exosomes
are related to the polarization of TAMs. Exosomal miR-1246
secreted from mutp53 colon cancer cells triggered M2 type
polarization of macrophages. The reprogramming TAMs promoted
anti-inflammatory immunosuppression by increasing the expres-
sion of TGF-β.86 Similarly, pancreatic cancer cells-derived exo- Fig. 3 The exosome-mediated metabolic reprogramming in the
somes induced M2 polarization of macrophages by activating cancer progression. Exosomes are vitally involved in tumor
PTEN/PI3Kγ pathway.87 Oppositely, a few studies have also shown proliferation, angiogenesis, metastasis, drug resistance, and immu-
nosuppression by metabolic reprogramming. Cancer-derived exo-
that tumor-derived exosomes triggered M1 polarization in somes can facilitate the proliferation of surrounding cancer cells via
macrophages.88,89 glycolysis. Meanwhile, exosomes can be transferred into the target
Importantly, macrophage polarization needs to be achieved by endothelial cells (ECs), which induced glycolysis and promoted
altering intracellular metabolism. M1 type expresses a high rate of angiogenesis activity in the ECs. Cancer cells-derived exosomes
glycolysis and requires lower oxygen supplement, which would increase glycolysis in stromal cells, which contribute to create the
help themselves to survive in the hypoxic microenvironment at pre-metastatic niche and facilitate the tumor metastasis. Addition-
sites of cancer and chronic inflammation. On the other hand, M2 ally, cancer-associated exosomes can lossen the ECs barriers by
type prefer to utilize OXPHOS and FAO.90,91 Furthermore, TAMs remodeling metabolism, which induces vascular permeability and
showed complex pattern changes of metabolism after influencing releases cancer cells into the bloodstream for metastasis. Moreover,
exosomes secreted by drug-resistant cancer cells could be
by different factors in the TME, including increased glycolysis, incorporated by drug-sensitive cells, thereby enhancing the
altered nitrogen cycle metabolism, and FAs synthesis.92 glycolysis and transferring the phenotype of drug-resistant to
Moreover, a recent study discovered a feed-forward loop drug-sensitive cancer cells. Notably, cancer-derived exosomes can
between TAMs and tumor cells through exosome-mediated induce immunosuppression by remodeling immune cell
metabolic reprogramming.93 TAMs enhance the aerobic glycolysis metabolism
and apoptotic resistance of breast cancer cells via the EVs
transmission of HISLA, which could block the hydroxylation and Proliferating cancer cells often absorb nutrients that exceed
degradation of HIF-1α in tumor cells. Reciprocally, lactate released bioenergy requirements and shunt metabolites to pathways that
from glycolytic tumor cells upregulates HISLA in macrophages.93 support biosynthesis. The metabolism of these cells is different
These results suggested that exosome-mediated metabolic from the metabolism of quiescent cells in its high rates of the
reprogramming is an important part of intercellular communica- aerobic glycolysis and biosynthesis of macromolecules.96
tions between immune and tumor cells. In a recent study, Shao and colleagues97 demonstrated that
irradiated lung cancer cells released exosomes to other lung
cancer cells, and facilitated the proliferation and growth of
EXOSOME-MEDIATED METABOLIC REPROGRAMMING IN recipient cells. Further research showed that exosomes containing
CANCER PROGRESSION the metabolic enzymes ALDOA and ALDH3A1 promoted uni-
A growing number of studies have shown that exosomes- rradiated lung cancer cells proliferation by accelerating glycolysis.
mediated metabolic reprogramming has a critical role in cancer The exosomal lncRNA SNHG3, as a sponge of miR-330-5p,
progression (Fig. 3). Exosomes deliver the biologically active positively regulated the expression of PKM, inhibited the OXPHOS,
substance to regulate the metabolic state of recipient cells and increased glycolysis, and promoted breast cancer cells prolifera-
facilitate tumor proliferation, angiogenesis, metastasis, drug tion.98 Another study found that miR-105-containing exosomes
resistance, and immunosuppression. In this section, we will derived from breast cancer cells could induce metabolic
introduce how exosomes affect cancer progression through the reprogramming in the CAFs. Additionally, CAFs displayed different
regulation of metabolism. metabolic profiles to promote cancer cells growth according to
the metabolic environment.53 Together, these findings indicate
Tumor proliferation that exosomes are important mediators of metabolic reprogram-
Cancer cell proliferation requires a massive accumulation of ming, thereby facilitating proliferation of cancer cells.
intracellular substances, such as proteins and lipids, to promote
cancer progression. Accumulating evidence showed that the Tumor angiogenesis
exosomes are rich in great content to contribute to cancer cells Angiogenesis is a complicated process by which the new
proliferation significantly. For example, exosomal EGFRvIII microvessels are formed from existing vessels, and it is involved
mRNA derived from glioblastoma patients’ serum, which in both pathological and physiological processes of the body.99
promoted the glioma cells proliferation.94 Another study Besides, tumor angiogenesis supply tumor with oxygen and
suggested that the moderately malignant pancreatic cell (PC) nutrients for continuous tumor growth, metastasis, and
line could incorporate exosomes from the highly malignant PC progression.100
line, and enhanced the proliferation of the former. Further- Recent studies have shown that cancer-associated exosomes
more, the exosomal zinc transporter (ZIP4) upregulation may exacerbate angiogenesis in cancer progression. The cargo of
be associated with the enhanced proliferation ability of exosome is enriched in angiogenesis-related factors, such as
recipient cells. 95 angiogenic proteins, miRNAs, mRNAs, and induces the phenotype

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changes and functions in ECs, which results in increased ability of It has been demonstrated that KSHV-infected cells transferred
EC proliferation, migration, and sprouting.101 virus-encoded miRNAs to surrounding cells by exosomes, leading
Glycolysis in ECs have a critical role in the process of to a metabolic shift toward the glycolysis in the non-infected
angiogenesis, because ECs rely on glycolysis rather than OXPHOS surrounding cells. In turn, the exosomes-mediated metabolic
to produce ATP for proliferation and migration.102,103 Moreover, reprogramming of the non-infected cells promoted the growth of
PFKFB3 is a key enzyme for glycolysis in ECs, which could promote infected cells, thereby accelerating the migration and progression
EC proliferation and angiogenic sprouting.102 of Kaposi’s sarcoma.106 Human melanoma-associated exosomal
It is well known that VEGF is one of the most important miR-210 and miR-155 produced by melanoma were incorporated
angiogenesis-related factors. Some studies have indicated that by normal stromal fibroblast cells, which led to increased aerobic
VEGF facilitates tumor angiogenesis by inducing a metabolic shift glycolysis and decreased OXPHOS in fibroblasts, and finally
from OXPHOS to glycolysis in ECs.104,105 Recently, Huang et al. resulting in extracellular acidification. Meanwhile, inhibition of
found that exosomes derived from AML cells could regulate miRNA activity reversed exosome-mediated metabolic reprogram-
vascular reprogramming in AML.72 VEGF-containing exosomes ming of stromal cells. Together, the stromal acidification
were transferred into the targeted ECs, and induced the contributed to creating the pre-metastatic niche via exosomes,
upregulation of glycolytic capacity and angiogenesis activity in and facilitated the tumor migration and invasion.114 Similarly, the
ECs through activating VEGF signaling.72 Virus-encoded micro- LMP1 in EVs could activate the fibroblasts to CAFs through NF-κB/
RNAs packed in exosomes from Kaposi’s sarcoma-associated p65 pathway, and aerobic glycolysis was increased in activated
herpesvirus (KSHV) infected cell were incorporated by the CAFs. Furthermore, EVs packaged LMP1 markedly increased the
neighboring cells, resulting in metabolism shifted toward the important pre-metastatic niche factors (S100A8, VEGFR1 and
glycolysis and reduced mitochondrial biogenesis in surrounding fibronectin) levels by stimulating CAFs in vivo favored the
non-infected cells. The exosomes supported the growth of establishment of pre-metastatic niche in nasopharyngeal carci-
infected cells by mediating the metabolic remodeling of noma.54 Primary prostate cancer (PCa) cells transferred exosomes
neighboring cells, thus promoting angiogenesis of Kaposi’s containing PKM2 into bone marrow stromal cell. Furthermore,
sarcoma.106 Obviously, these studies show that exosomes play a CXCL12, an important promoter of bone metastasis in PCa, could
critical role in angiogenesis through transferring angiogenic be induced by an exosome-mediated HIF1α-dependent pathway,
factors or miRNA to regulate the angiogenic function of ECs by which created a pre-metastatic niche and promoted the progres-
metabolic reprogramming. sion of PCa metastasis.80 In breast cancer, large exosomes secreted
from cancer cells were found to contain miR-122, which could
Tumor metastasis remodel metabolism in the pre-metastatic niche to exacerbate
Metastasis is a critical stage of cancer progression, remaining to be metastasis.115 Breast cancer cells could suppress uptake of glucose
a major challenge in treatment of cancer and a leading cause of by stromal cell in pre-metastatic niche of brain and lung, by
cancer-related mortality. The cascade of metastasis consists of a transferring exosomes that carried enriched miR-122. Then, miR-
series of sequential steps, and cancer cells must complete before 122, incorporated by non-tumor cell in pre-metastatic niche,
they can disseminate to secondary organs. After beginning with targeted PKM2 and inhibited glycolysis, which could reduce the
local invasion of adjacent tissue, the cancer cells invade the utilization of glucose through niche cells and allow the cancer cell
circulation through blood vessels or the lymphatic system, then to utilize glucose. In addition, a study has found that exosomes
disseminate to the different distant organs, and finally, they containing VEGF could enhance glycolysis of ECs.71 VEGF signaling
successfully colonize in the distant secondary organs.13 could loosen tight junctions between ECs, which induced vascular
Evidence indicates that cancer-derived exosomes are participat- permeability and increased cancer cells transendothelial migra-
ing in critical steps of the metastasis in the primary tumor. tion.69 Another study has also demonstrated that cancer-derived
Exosomes promote tumor metastasis by enhancing cancer cells exosomes could remodel the ECs by destroying the function of
invasion and migration, reprogramming the extracellular endothelial cell barriers and inducing vascular permeability, which
matrix.107 Additionally, cancer-derived exosomes induce multiple releasing cancer cells into the bloodstream for metastasis.71 These
cell populations and recruit them to secondary organ sites. The findings reveal that the non-tumor cells that take up the exosomes
interactions among these exosomes, local stromal cells and secreted by the cancer cells regulate the remodeling of
cancer-recruited cells may create a favorable microenvironment metabolism, which promote the tumor metastatic capacity. Taken
for tumor metastasis.7 The establishment of pre-metastatic niche together, exosomes-mediated metabolic reprogramming may be
is the precondition that supports the distal settlement of cancer a critical mechanism to exacerbate migration and metastasis.
cells and promotes metastasis. Meanwhile, angiogenesis and
lymphangiogenesis, immunosuppression, and reprogramming are Tumor drug resistance
all vital features of pre-metastatic niche.108 The development of tumor drug resistance remains a major
Cancer cells experience strong selective pressure during barrier to the therapeutic effect. It is currently known that tumor
metastatic cascade, while metastatic cancer cells need to undergo drug resistance mechanisms include drug efflux, altered drug
heightened oxidative stress.109 Cells detachment induce a large metabolism, altered energy programming, DNA damage repair,
amount of ROS, and excessive ROS can cause cell death, namely cancer stem cells, and epigenetic alterations.116
anoikis, which is an obstacle to metastasis.110 ROS is mainly Evidence suggests that exosomes have emerged as critical
derived from the oxidative metabolism of mitochondria. The player in the onset and development of tumor drug resis-
Warburg effect may reduce the production of mitochondrial ROS, tance.117,118 Because the drug susceptibility is different in tumor
and increase glycolysis while also enhancing the pentose cells, exosomes secreted by drug-resistant tumor cells were
phosphate pathway to produce NADPH, which is vital for transferred to drug-sensitive cells, which might also increase the
antioxidant activity.111 By limiting the oxidative metabolism of resistance of the susceptible tumor cells.119,120
mitochondria, the “Warburg effect” decreases oxidative stress. The metabolic reprogramming and drug resistance are closely
Additionally, glucose is metabolized to lactate and pyruvate via correlative. The enhanced glycolysis of the tumor results in
glycolysis, and excess lactate production leads to acidic TME.112 In increased lactate and H+ production, which could lead to the
vivo study has shown that extracellular acidification favored acidosis of the TME. Moreover, the TME acidosis has been reported
metastasis of melanoma cells.113 Similarly, another study sug- to contribute to drug resistance.121,122
gested that local stromal acidification promoted the formation of Wang et al. demonstrated that exosomes secreted by chemore-
pre-metastatic niche in melanoma.114 sistant colorectal cancer cells could be incorporated by

Yang et al.
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chemosensitive cells, thereby enhancing the glycolysis and cells (MDSCs).131 In addition to glucose metabolism, amino acid
chemoresistance.119 Similarly, another study showed that exo- metabolism is also recognized to play a vital role in immunosup-
somes with high acid SMase (ASM) content were able to transfer pression. Arginine (Arg) metabolism is an important pathway in
the phenotype of drug-resistant to drug-sensitive multiple regulating immune cell reactivity, and two key enzymes are
myeloma cells through regulating lipid metabolism. After anti- involved in the mechanism of immune escape: nitric oxide
myeloma drug stimulation, ASM expression and protein levels synthase (NOS) and arginase (ARG). Overexpression of NOS or ARG
were increased in multiple myeloma cells and their exosomes, in tumor cells leads to Arg consumption in the TME and inhibits T-
which reflected the tumor-protective effect of ASM and promoted cells proliferation and function.132 Glutamine exhaustion by clear
the development of drug resistance.120 Moreover, Huang and cell renal cell carcinoma (ccRCC) cells induce macrophages to
colleagues72 indicated that AML-secreted exosomes increased secrete IL-23 via the activation the HIF1α pathway. IL-23 activates
glycolysis in ECs, and resulted in the remodeling of vascular and regulatory T cells (Treg) and promotes the expression of IL-10 and
the acquisition of chemoresistance. Recently, Petanidis S et al.122 TGF β, thereby inhibiting T-cell cytotoxic activity and mediate
isolated exosomes from patients with Kras chemoresistant lung immune escape.133 In lipids metabolism, fatty acid synthase
cancer patients.122 Exosomes can remodel metabolism in a PKM2- (FASN) is a critical metabolic enzyme in the de novo synthesis of
dependent manner to maintain lung cancer cell metabolic fatty acids. Jiang et al.134 found that the overexpression of FASN in
chemoresistance.122 Therefore, these data show that exosomes ovarian cancer leads to lipids accumulation in the TME, causing
secreted by the cancer cells promote the drug resistance by T cells dysfunction, which in turn induces impaired anti-tumor
remodeling the metabolism. In turn, targeting exosomes may immune response. In the TME, cancer cells product metabolic
become a new target for tumor drug-resistant therapy. byproducts by metabolic reprogramming, including lactate, ROS,
nitric oxide, prostaglandin, and arachidonic acid, resulting in an
Tumor immunosuppression inflammatory microenvironment.135 Inflammatory cells may influ-
Cancer progression is intimately related to the dysregulation of ence, and be influenced by, cancer cells metabolism, primarily
immune cell subsets and chronic inflammation. In the environ- glucose metabolism, and promote tumor growth and immune
ment of chronic inflammation, multiple complex mechanisms escape through metabolic pathways.123
mediated by inflammatory cells contribute to cancer develop- A recent study by Basso et al. reported the effects of exosome-
ment. Inflammation is closely linked to immunity, and the same mediated metabolic reprogramming on tumor immunosuppres-
immune cells population causes both immune response and sion. Pancreatic ductal adenocarcinoma (PDAC)-secreted exo-
inflammation.123 somes from cells without the expression of SMAD4 could create
Cancer cells-derived exosomes promote the induction of an immunosuppressive myeloid cells background by increasing
immunosuppression and inflammation, facilitating cancer pro- glycolysis and calcium flux through transferring differentially
gression. NKG2D, an activated cytotoxicity receptor, plays a vital expressed miRNA and protein associated with SMAD4.136 These
role in immunosuppression in the tumor. Lundholm et al. results suggested that immunosuppression induced by exosome-
identified that exosomes derived from prostate cancer cell mediated metabolic reprogramming could be a potential inducer
expressed NKG2D ligands on their surface, which could induce of tumor progression.
the downregulation of NKG2D on natural killer (NK) cells and
CD8 + T cells. The downregulation of NKG2D on natural killer (NK)
cells and CD8 + T cells resulted in the impairment of their THE UNDERLYING MOLECULAR MECHANISM OF EXOSOME-
cytotoxic function, thereby promoting immunosuppression and MEDIATED METABOLIC REPROGRAMMING IN TME
tumor immune evasion.124 Furthermore, exosomes transfer REMODELING
immunosuppressive molecules from cancer cells to immune cells, In the intercellular communication, exosomes mediate the
which promote cancer progression by suppressing the function of exchange of biologically active molecules between cells and
immune cells.125 TGF-β is one of the major immunosuppressive remodel the biological characteristics of recipient cells. Recently,
cytokines. Exosomes derived from BC cells suppressed T cells accumulating evidence has shown that exosomes have been
proliferation through TGF-β, which inhibited immune response.126 recognized as crucial mediators in the metabolic reprogramming
A recent study demonstrated that human melanoma-secreted of cancer cells and stromal cells. To determine how exosomal
exosomes carried immunosuppressive programmed cell death cargoes influence the metabolic reprogramming in the TME, in
ligand 1 (PD-L1), inhibited the function of CD8 T cells, and this section, we will discuss the contents in exosomes from cancer
exacerbated tumor growth.127 Meanwhile, exosomes released by cells and stromal cells in the TME (Table 1), such as exosomal
cancer cells also promote the mediation and persistence of proteins, miRNAs, ncRNAs, and metabolites, as well as the
inflammation. Exosomes-mediated pro-tumor inflammation underlying mechanisms by which exosomes affect metabolic
through Toll-like receptor (TLR) signaling. For example, lung reprogramming.
cancer cells secreted exosomal miR-21 and miR-29a, which could
bind to TLR8 and stimulate the activation of NF-κB, leading to Exosomal proteins
product the pro-inflammatory cytokines and promote tumor Proteins are the main components in exosomes. Of note, previous
proliferation and metastasis.128 Exosomes containing hY4 derived proteomic study showed that glucose metabolism-associated
from chronic lymphocytic leukemia (CLL) could be transferred to proteins were enriched in exosomes from cancer cells.137 The
monocytes leading to key CLL-related phenotypes, including the GLUT1 affects the absorption and utilization of glucose, which is a
release of the cytokines IL-6, CCL2, CCL4, and the promotion of rate-limiting transporter for glucose uptake. PKM2 is a glycolytic
PD-L1 expression. Moreover, exosomes-mediated transferred hY4 enzyme that has been recognized as crucial mediator in the
to monocyte facilitate cancer-related inflammation and immune glycolytic pathway. In addition, several studies have found that
escape through the upregulation of PD-L1.129 exosomes contained GLUT1 and PKM2.80,138 Wan et al.138 showed
It has been shown that cancer cells with high glycolytic activity that enriched PKM2 and GLUT1 were secreted in exosomes from
have a strong ability to escape immune surveillance, due to T-cells activated hepatic stellate cells (HSCs), which induced the
are impaired in their ability to kill cancer cells. However, inhibition “Warburg effect” of quiescent HSCs, Kupffer cells (KCs) and liver
of glycolysis improved the anti-tumor immunity of T cells.130 sinusoidal endothelial cells (LSECs); meanwhile, inhibition of Hif-1
Meanwhile, the glycolytic metabolite, lactate, could directly inhibit by 2-ME (an inhibitor of Hif-1) or specific siRNA suppressed the
the cytolytic activity of NK cells and indirectly inhibit NK cells expression of PKM2 and GLUT1 in exosomes from LPS- or hypoxia-
function by increasing the number of myeloid-derived suppressor activated LX-2 cells. Another study showed that prostate cancer-

8
Table 1. Overview of exosomal cargoes and functions in cancer
Cargoes type Exosomal cargoes Donor cells Recipient cells Function Ref.
138
Protein PKM2, GLUT1 LPS-activated LX-2 and activated primary HSCs HSCs, KCs, and LSECs Induces the glycolysis of quiescent HSCs LSECs and KCs
80
PKM2 LNCaP, PC3, and C4-2B ST2, mouse BMSCs Creates a pre- metastatic niche through transferring PKM2
72
VEGF HL-60, U937, primary AML cells HUVECs Promotes chemoresistance by inducing the glycolysis
in HUVECs
97
ALDOA, ALDH3A1 Irradiated A549 and NCI-H446 Unirradiated A549 and NCI-H446 Enhances the motility of the recipient cells by promoting the
glycolysis
54
LMP1 CM CAFs Increases the glycolysis and autophagy in CAFs
52
ITGB4 MDA-MB-231, BT-20 CAFs Promotes the glycolysis and the export of lactate in CAFs
67
FAO-related proteins Adipocytes SKMEL28 and 1205Lu Promotes tumor aggressiveness by inducing fatty acid
oxidation
139
AM PC patient-derived cell lines Adipocytes Induce lipolysis
53
miRNA miR-105 MCF10A and MDA-MB-231 NIH3T3 and WI-38 Promotes tumor growth by reprogramming the metabolism
of CAFs
115
miR-122 MCF10A and MDA-MB-231 Mouse lung fibroblasts and Mouse Remodels metabolism of the niche cells to promote tumor
astrocytes progression
64
miR-155 4 T-1, C2C12 and HEK 293T 3 T3-L1 Induces the beige/brown differentiation and promotes
lipolysis in the adipocytes
106
miRNAs KSHV-infected LECs HUVEC and LEC Promotes the glycolysis in the non-infected cells.
114
Yang et al.
miR-155, miR-210 1770-Her4, 2183-Her4, 1300-mel, HMCB, 526-mel, HADF Promotes the tumor metastasis through enhancing the
888-mel, and Hs 294T glycolysis in stromal cells
65
miR-126, miR-144 MCF-7, MDA-MB-231, and HEK 293T 3T3-L1 Inducing the metabolic reprogramming in adipocytes to
promote tumor progression
98
lncRNA SNHG3 Breast cancer patient-derived fibroblast cells MCF-7 and MD-MBA-453 Promotes the tumor growth by reprogramming the
metabolism of breast cancer cells
93
HISLA TAMs MDA-MB-231, MDA-MB-468, BT-474, Enhances the glycolysis and chemoresistance of breast
and MCF-7 cancer cells
119
circRNA ciRS-122 SW480/oxaliplatin (L-OHP) and HCT116 /L-OHP SW480 and HCT116 Increases the glycolysis and decreases drug sensitivity in the
sensitive cancer cells
144
Metabolite Lactate, glutamate hMSCs MCF-7 Promote the tumor growth

Yang et al.
9
secreted exosomes transferred PKM2 protein to stromal cells process.64 A study from Yogev et al.106 reported that KSHV-
rather than inducing PKM2 mRNA synthesis or protein synthesis, infected cells transferred the miRNAs to surrounding cells through
which increased CXCL12 production in the stromal cells to create a secreting exosomes, which resulted in a metabolic reprogram-
pre-metastatic niche.80 VEGF is an important angiogenesis factor. ming toward the glycolysis, decreased mitochondrial biogenesis
The study from Wang et al.72 showed that VEGF transferred by and the stabilization of HIF1α in the non-infected cells. In addition,
AML cells derived exosomes activated VEGF signaling pathway in Shu et al.114 observed that exosomes secreted by human
HUVECs, resulting in inducing proliferation and tube formation in melanoma cells, including enriched miR-155 and miR-210,
HUVECs through promoting glycolysis, in turn, which promoted remodeled stromal cells metabolism and might induce formation
the chemoresistance of AML cells. Shao and colleague97 demon- of pre-metastatic niche to promote tumor metastasis by enhan-
strated that metabolic enzymes ALDOA and ALDH3A1 were cing aerobic glycolysis and suppressing OXPHOS in stromal cells.
increased in exosomes released by irradiated lung cancer cells, Wu and colleagues found that IRS1 is the direct target of miR-126,
and exosomes secreted from irradiated cancer cells transferred and the exosomal miR-126 derived from breast cancer cells
the metabolic enzymes to the unirradiated cancer cells, which induced metabolic reprogramming in adipocytes, including
enhanced the motility of the recipient cells through accelerating inducing the catabolism after the disruption of IRS/Glut-4 signaling
glycolysis. Moreover, EVs packaged LMP1 secreted by nasophar- pathways, activating the AMPK/autophagy pathways and stabiliz-
yngeal carcinoma (NPC) activated normal fibroblasts into CAFs ing the expression of HIF1α. Meanwhile, this study also demon-
through the NF-κB/p65 pathway, and increased aerobic glycolysis strated breast cancer cells-secreted exosomal miR-144 mediated
and autophagy in activated CAFs. Meanwhile, the CAFs upregu- the beige/brown differentiation of adipocyte via the MAP3K8/
lated the expression of MCT4 through activation of p65 pathway, ERK1/2/PPARγ axis. Moreover, inhibition of miR-126 or miR-144
which could export β-HB and lactate to MCT1-expressing cancer decreased adipocyte-induced tumor progression in vivo, which
cells. The uptake of β-HB and lactate by cancer cells enhances the revealed exosomal miR-126 and miR-144 from the tumor-
OXPHOS, which could promote the tumor progression and induce adipocyte crosstalk remodeled systemic energy metabolism to
radiation resistance of tumor both in vitro and in vivo.54 Integrin promote tumor progression.65
beta 4 (ITGB4) overexpression has emerged as critical player in
cancer progression. Sung and colleagues52 found that the triple- Exosomal lncRNA and circRNA
negative breast cancer (TNBC) cells-derived exosomal ITGB4 In addition to microRNAs, other non-coding RNA (ncRNA) classes
proteins induced BNIP3L-dependent mitophagy and enhanced such as lncRNAs and circRNAs have been investigated. Li et al.
expression of MCT4, which promoted the glycolysis and the found that CAFs-derived exosomal lncRNA SNHG3 remodeled the
export of lactate in CAFs. Some studies have found FAO-related metabolism after breast cancer cells uptake exosomes. In addition,
proteins in adipocytes-derived exosomes through proteomics SNHG3 acted as a sponge of miR-330-5p. Moreover, miR-330-5p
analysis, and these exosomes could induce metabolic reprogram- targeted PKM and regulated by SNHG3 in breast cancer cells.
ming in melanoma cells for the benefit of FAO.67,68 Another study Mechanistically, knockdown of exosomal SNHG3 suppressed
showed pancreatic cancer (PC) cells-secreted exosomes contain- breast cancer growth and glycolysis in vivo and in vitro through
ing adrenomedullin (AM) interacted with adrenomedullin recep- up-regulating miR-330 and decreasing the expression of PKM.
tors (ADMRs) in adipocytes, and activated MAPKs p38 and ERK 1/ These results demonstrated that CAFs-released exosomal lncRNA
2 signaling pathways and induced lipolysis through HSL could remodel breast cancer cell metabolism and promoted the
phosphorylation.139 tumor growth.98 Another study from Chen and collaborators
reported TAMs enhanced the apoptosis resistance and the
Exosomal microRNAs glycolysis in breast cancer cell through transmitting EVs-
Recently, exosomal microRNAs have been implicated in inter- packaged lncRNA HISLA. It had also been shown that blocking
cellular communication. Yan et al. observed that exosomal miR- TAMs-secreted HISLA in EVs, which inhibited chemoresistance and
105 derived from breast cancer cells could activate MYC pathway aerobic glycolysis of breast cancer in vivo. In addition, lncRNA
in CAFs to induce a metabolic reprogramming. Moreover, CAFs HISLA bound prolyl hydroxylase domain 2 and inhibited its
could display different metabolic profiles depending on the interaction with HIF-1α, which prevented hydroxylation and
metabolic environment. When nutritionally adequate, the exoso- degradation of HIF-1α. Intriguingly, lactates exported from cancer
mal miR-105 reprogrammed CAFs with enhanced glycolysis and cell upregulated HISLA in TAMs and promotes the feed-loop
glutaminolysis, thereby providing fuel to the neighboring cancer between TAMs and cancer cells.93 Recently, Wang et al. showed
cells. When at a low nutrient level and metabolic byproduct that oxaliplatin-resistant colorectal cancer cells-derived exosomal
accumulate, CAFs converted metabolic waste products (including ciRS-122 was a sponge of miR-122, which enhanced PKM2 protein
lactate and ammonium) into energy-rich metabolites, which expression, thus increased the glycolysis and decreased the drug
contributed to promoting tumor growth.53 Fong and collaborators sensitivity in the sensitive cancer cell. Meanwhile, it also indicated
found that breast cancer cell-secreted exosomal miR-122 could that exosomal si-ciRS-122 reversed the oxaliplatin resistance
suppress the glucose uptake by the niche cells through down- through inhibiting the ciRS-122/miR-122/PKM2 axis in vivo and
regulating PKM2 and GLUT1. Meanwhile, inhibition of exosomal in vitro.119
miR-122 could rescue glucose metabolism in distant organs, such
as lungs and brain, and decreased the incidence of tumor Exosomal metabolites
metastasis in vivo, which demonstrated that exosomal miR-122 Exosomal metabolites have also emerged as important players in
was able to remodel systemic energy metabolism to promote tumor progression. Although the exosomal contents of are similar
tumor progression.115 In another study, Wu et al. showed that miR- to the donor cells, they are enriched in certain lipids, including
155 directly targets peroxisome proliferators-activated receptor γ cholesterol, phosphatidylinositol, and phosphatidylcholine, and
(PPARγ). The exosomal miR-155 derived from breast cells act as lipid mediators of intercellular transmission.140 Moreover,
mediated the beige/brown differentiation and promoted lipolysis the enrichment of specific lipids in exosomes significantly
in the adipocytes by downregulating the expression of PPARγ. In increases the membrane stiffness of the exosomes. These lipids
contrast, glycolysis was not significantly influenced by the are present in the outer membrane of the exosome, and play a
exosomal miR-155 in the cancer cells. This study also proved that crucial role in the recognition and internalization of the exosome,
cancer cells co-cultivated with mature adipocytes stimulated the which allows the exosomes to deliver the metabolites to the
aggressive phenotype by inducing EMT. It could be speculated recipient cells.141 The exosomes carry bioactive lipids, such as
that exosomal miR-155 was associated with the tumor-promoting leukotrienes and prostaglandins, which promote cancer

Yang et al.
10
Table 2. Metabolism-related exosome from biofluids as diagnostic biomarkers in cancer
Biomarker Cancer type Biofluids Method Clinical value Ref.

119
ciRS-122 and miR- Colorectal cancer Serum Western blot, RT-qPCR Expression levels of ciRS-122 are positively correlated with drug
122 resistance.
93
HISLA Breast cancer Plasma qRT–PCR Diagnostic biomarker of chemoresistance for breast cancer.
139
AM Pancreatic cancer Plasma Western blot Diagnostic biomarker for early detection of PC
progression.142 Moreover, exosomes derived from cancer cells mainly focus on inhibiting the production and secretion of
carry glycosidases, which can cleave the extracellular matrix (ECM) exosomes, blocking exosome-mediated intercellular communica-
components, such as glycoproteins and proteoglycans, resulting tion, and eliminating the specific exosomal active molecular. The
in ECM remodeling and facilitating tumor development.143 A nSMase2 inhibitor, GW4869, is widely used to suppress the
metabolomics study showed glutamate and lactate in the EVs of secretion of exosomes, which significantly inhibit the production
human mesenchymal stem cells (hMSCs). Glutamate could of exosomes.145 There is growing evidence that metabolic
provide precursors for the major macromolecular classes via reprogramming is an important mechanism influencing cancer
carbon and nitrogen trafficking, and lactate could enhance the progression. Therefore, finding an effective way to inhibit
ability of cancer cells to survive in the hypoxic and nutrient- metabolic reprogramming and thus treat cancer is a potential
deficient conditions.144 new approach.
As discussed in this paper, the latest evidence confirms that the
exosomal pathway is important for tumor metabolic reprogram-
THE POTENTIAL APPLICATION OF EXOSOME ming. So, we speculate that targeting regulation of exosomal-
Exosome targeting metabolic reprogramming as diagnostic related mechanisms may be able to treat cancer by affecting
biomarker metabolic reprogramming. Recently, Li et al. demonstrated that
Increasing evidence shows that exosomes hold enormous CAFs-derived exosomes enhanced glycolysis, inhibited mitochon-
potential for diagnosis, prognosis, and evaluation of efficacy in drial OXPHOS, and promoted the proliferation of breast cancer
tumor. Exosomes are easily obtained from most body fluids, cells. However, the GW4869 could reverse the metabolic changes
including blood, saliva, urine, and ascites, which can act as of breast cancer cells, which in turn led to inhibit the cancer
promising biomarkers in tumor “liquid biopsy”.9 The exosomal progression.98 Another study also showed that the secretion of
cargoes are encapsulated by a lipid bilayer membrane, which exosomes was blocking by GW4869, which inhibited the glycolysis
protects the exosomal contents to prevent them from degrading and activation of recipient cells.138 Wang et al.119 found that
during transportation. The biologically active molecules contained exosomes could act as gene delivery vesicles transferring short
in exosomes reflect the different pathological states of cells origin interfering RNA (siRNA) to target cancer cells, which inhibited
and can remodel the metabolism of the recipient cells, therefore glycolysis and reversed oxaliplatin resistance in drug-resistant
providing a rich source of biomarkers (Table 2). colorectal cancer cells. According to this biological characteristic
Wang et al. discovered exosomal ciRS-122 from the serum of of exosomes, Shu et al.114 discovered that exosomes transferred
oxaliplatin-resistant colorectal cancer patients and oxaliplatin- with miRNA inhibitors could reverse the exosome-mediated
sensitive patients. Compared with the oxaliplatin-sensitive group, metabolic reprogramming, which could reduce the risk of tumor
the oxaliplatin-resistant group had higher ciRS-122 expression metastasis. Notably, exosomes have multiple advantages as
levels in the exosomes. Moreover, Exosomal ciRS-122 derived from potential therapeutic targets owing to their crucial role during
drug-resistant colorectal cancer cells could enhance the glycolysis tumor progression. Although many in vitro studies targeting
to reduce drug sensitivity in drug-sensitive cells, which revealed exosomes have been performed to treat cancers, few clinical trials
that exosomal ciRS-122 could regulate metabolism to favor tumor have been conducted. We speculate that targeted therapy aiming
drug resistance.119 In our opinion, exosomal ciRS-122 targeting to suppress the production and transfers of exosomes would be a
metabolism might be a candidate for predicate tumor drug potent way to inhibit tumor progression, especially tumor
resistance in colorectal cancer. Recently, Chen et al. found that the metastasis. Targeting exosomes combined with targeting cancer
expression level of EVs-packed lncRNA HISLA in plasma of breast cells have a promising effect on inhibiting cancer progression,
cancer patients is closely correlated with the level of HISLA in which may be a potential treatment strategy for future tumor
tumor-associated macrophages isolated from the breast cancer treatment.
samples. In addition, HISLA expression level was associated with
glycolysis, poor chemotherapy effect, and low survival rate of
breast cancer patients, indicating EVs-packed HISLA as an CONCLUSION
independent prognostic biomarker in breast cancer patients.93 Exosomes secreted from cancer cells and their surrounding
Another study revealed that adrenomedullin (AM) was signifi- stromal cells can be incorporated by the recipient cells to
cantly upregulated in plasma exosomes from patients with communicate with each other, which results in metabolic changes
pancreatic cancer (PC) compared to non-PC control patients. in the TME. As mentioned above, exosomes are implicated in
Moreover, PC-exosomal AM induced lipolysis in subcutaneous metabolic reprogramming and microenvironment remodeling,
adipocytes of PC patients demonstrated that exosomal AM could which profoundly exacerbate tumor angiogenesis, metastasis, and
be a potential early diagnostic biomarker of pancreatic cancer drug resistance. The existing researches have partially clarified the
patients.139 These findings suggest that the exosomes may be mechanism of exosomes in the TME, mainly attributed to the
concerned as promising diagnostic and prognostic biomarkers for specific biologically active substances they carry. In particular, in
cancer therapy by targeting metabolic reprogramming. the TME, there seems to be a bi-directional transfer of cargos
between cancer cells and stromal cells. Exosomes derived from
Exosome-mediated metabolic reprogramming as therapeutic cancer cells remodel the metabolism of stromal cells, thereby
target facilitating cancer progression; on the other hand, cancer-
The specific biological contents of exosomes profoundly facilitate associated stromal cells secreted exosomes that can also affect
the cancer progression. Thus, the current therapeutic strategies tumor development by regulating cancer cells metabolism.

Yang et al.
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Exosome-mediated metabolic reprogramming: the emerging

Signal Transduction and Targeted Therapy (2020)5:242 ; https://doi.org/10.1038/s41392-020-00359-5

INTRODUCTION other biologically active constituents. The role of exosomes in

Received: 5 August 2020 Revised: 11 September 2020 Accepted: 27 September 2020

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Signal Transduction and Targeted Therapy (2020)5:242

Signal Transduction and Targeted Therapy (2020)5:242

Signal Transduction and Targeted Therapy (2020)5:242

Signal Transduction and Targeted Therapy (2020)5:242

Signal Transduction and Targeted Therapy (2020)5:242

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Signal Transduction and Targeted Therapy (2020)5:242

Biomarker Cancer type Bioﬂuids Method Clinical value Ref.

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Signal Transduction and Targeted Therapy (2020)5:242

Signal Transduction and Targeted Therapy (2020)5:242

Signal Transduction and Targeted Therapy (2020)5:242

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