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STING

Stimulator of interferon genes (STING) can promote tumor inflammation and antitumor immunity. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment.

Expression and normal function

STING is an intracellular protein expressed in antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, as well as other cell types^1,2
STING is an innate immune activator that stimulates APCs to drive cytotoxic T-cell activity²

It is triggered when an intracellular-sensing protein detects DNA from pathogens or dying tumor cells^3,4

Activation of STING leads to the production and secretion of proinflammatory cytokines that increase antitumor immunity, such as interferons (IFNs) and tumor necrosis factor alpha (TNFα)^3,5

IFNs promote tumor inflammation by stimulating APCs to activate
T cells, initiating T-cell proliferation and trafficking to the tumor microenvironment^6,8
IFNs can also amplify the antitumor function of natural killer (NK) and cytotoxic T cells, as well as promote memory T-cell survival^2,9,10

STING can also stimulate activation of the NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome, leading to the production of additional cytokines¹¹

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Role in cancer

Reduced STING expression may be associated with increased metastasis of tumor cells^12-14

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Preclinical evidence

Preclinical data suggest that activation of STING can increase T-cell priming, leading to increased T-cell activation and an inflamed tumor microenvironment^4,6-8
Furthermore, mouse models indicate that activation of STING along with blockade of immune checkpoint receptors may synergistically promote the antitumor immune response^15,16

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REFERENCES–STING

1. Barber GN. STING-dependent cytosolic DNA sensing pathways. Trends Immunol. 2014;35(2):88-93. 2. Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-2411. 3. Corrales L, Gajewski TF. Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer. Clin Cancer Res. 2015;21(21):4774-4779. 4. Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830-842. 5. Curran E, Chen X, Corrales L, et al. STING pathway activation stimulates potent immunity against acute myeloid leukemia. Cell Rep. 2016;15(11):2357-2366. 6. Corrales L, Glickman LH, McWhirter SM, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11(7):1018-1830. 7. Woo S-R, Corrales L, Gajewski TF. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 2015;36(4):250-256. 8. Ohkuri T, Ghosh A, Kosaka A, et al. STING contributes to anti-glioma immunity via triggering type-I IFN signals in the tumor microenvironment. Cancer Immunol Res. 2014;2(12):1199-1208. 9. Swann JB, Hayakawa Y, Zerafa N, et al. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J Immunol. 2007;178(12):7540-7549. 10. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15(7):405-414. 11. Gaidt MM, Ebert TS, Chauhan D, et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell. 2017;171(5):1110-1124. 12. Song S, Peng P, Tang Z, et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci Rep. 2017;7:39858. doi:10.1038/srep39858. 13. Xia T, Konno H, Ahn J, Barber GN. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 2016;14(2):282-297. 14. Xia T, Konno H, Barber GN. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Res. 2016;76(22):6747-6759. 15. Fu J, Kanne DB, Leong M, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. 2015;7(283):283ra52. doi:10.1126/scitranslmed.aaa4306. 16. Ghaffari A, Peterson N, Khalaj K, et al. STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer. Br J Cancer. 2018;119(4):440-449.