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STING: infection, inflammation and cancer

Nature Reviews Immunology volume 15, pages 760–770 (2015)Cite this article

Subjects

Key Points

  • Stimulator of interferon genes (STING) is activated by binding to cyclic dinucleotides (CDNs), which results in potent cytokine production. CDNs are produced by certain intracellular bacteria and are generated by the cyclic GMP–AMP synthase (cGAS) following binding to cytosolic DNA species, such as viral DNA.

  • STING-inducible innate immune molecules are essential for protection of the host against pathogens and are important for the stimulation of adaptive immunity.

  • Self-DNA, for example from the nucleus or mitochondria, can leak into the cytosolic compartment and stimulate STING activity to cause autoinflammatory disease. Certain mutations in the gene encoding STING can cause the protein to become permanently active and similarly induce autoinflammatory responses.

  • STING can be activated in phagocytes by DNA released from engulfed tumour cells and drive the production of cytokines necessary for generating robust antitumour T cell responses.

  • DNA-damaging agents can cause the release of nuclear DNA into the cytosol that stimulates STING-dependent cytokine production and phagocyte infiltration. This may be essential for eliminating damaged cells and generating antitumour T cell responses, but chronic stimulation may also promote inflammation-aggravated cancer.

  • STING agonists exert potent antitumour activity and may be effective, novel adjuvants in vaccine formulations. In contrast, inhibitors of STING signalling may be beneficial for the treatment of autoinflammatory disease, such as systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI).

Abstract

The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications — not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.

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Figure 1: STING-dependent innate immune signalling.
Figure 2: STING signalling is essential for anti-pathogen host defence.
Figure 3: STING in autoinflammatory disease.
Figure 4: STING control of tumour development.

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Authors and Affiliations

  1. Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Glen N. Barber

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  1. Glen N. Barber
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Glossary

Stimulator of interferon genes

(STING). An endoplasmic reticulum-associated protein that binds to cyclic dinucleotides or cytosolic DNA to trigger cytokine production.

Cyclic dinucleotides

(CDNs). Secondary messengers secreted by certain bacteria, such as Listeria monocytogenes, or generated by cyclic GMP–AMP synthase (cGAS) following binding to cytosolic DNA.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B and T cell function. SLE can be associated with hyperproduction of type I interferons.

Aicardi–Goutières syndrome

(AGS). A neurodegenerative disorder that can be caused by STING-dependent cytokine hyperproduction owing to mutations in genes such as TREX1 (three-prime repair exonuclease 1).

Cyclic GMP–AMP synthase

(cGAS). A cellular protein that binds to cytosolic DNA species and generates stimulator of interferon genes (STING)-activating cyclic dinucleotides.

Oligoadenylate synthetase 1

(OAS1). A double-stranded RNA sensor that, in the presence of ATP, generates 2′,5′-linked oligoadenylates, which can activate RNase L-mediated viral RNA degradation.

Translocon-associated protein

(TRAP). A complex of proteins that shunt proteins destined for N-linked glycosylation and secretion into the endoplasmic reticulum after translation.

Immune complexes

Complexes of antigen (including DNA) bound to antibody and, sometimes, components of the complement system. The levels of immune complexes are increased in many autoimmune disorders, in which they become deposited in tissues and cause tissue damage.

MicroRNAs

(miRNAs). Small RNA molecules that regulate the expression of genes by binding to the 3′ untranslated regions (3′ UTR) of specific mRNAs.

Three-prime repair exonuclease 1

(TREX1). A DNase that degrades self-DNA species that can otherwise chronically activate stimulator of interferon genes (STING) signalling.

Damage-associated molecule pattern

(DAMP). A cellular molecule, such as uric acid, ATP and heat shock proteins, that can activate the inflammatory response in the absence of infection.

Mitochondrial outer-membrane permeabilization

(MOMP). Permeablization induced by virus infection and/or apoptosis to release mitochondrial DNA that could conceivably activate stimulator of interferon genes (STING).

Angiogenesis

The development of new blood vessels from existing blood vessels. It is frequently associated with tumour development and inflammation.

Checkpoint blockade

The targeting of T cell co-inhibitory receptors, such as cytotoxic T lymphocyte antigen 4 (CTLA4) or programmed cell death protein 1 (PD1), by antibodies that have clinical activity in multiple cancer types.

Cross-presentation

The initiation of a CD8+ T cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.

Ataxia telangiectasia

A neurodegenerative disease caused by mutations in the ATM (ataxia-telangiectasia mutated) gene, the product of which is essential for the recognition and repair of DNA breaks.

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Barber, G. STING: infection, inflammation and cancer. Nat Rev Immunol 15, 760–770 (2015). https://doi.org/10.1038/nri3921

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