Ovarian cancer is the leading cause of mortality due to gynecologic malignancy. The majority of women diagnosed with the most common subtype, high-grade serous ovarian carcinoma (HGSC), develop resistance to conventional therapies despite initial response to treatment. HGSC tumors displaying DNA damage repair (DDR) gene deficiency and high chromosomal instability mainly associate with higher cytotoxic immune cell infiltration and expression of genes associated with these immune pathways. Despite the high level of immune infiltration observed, the majority of patients with HGSC have not benefited from immunomodulatory treatments as the mechanistic basis of this infiltration is unclear. This lack of response can be primarily attributed to heterogeneity at the levels of both cancer cell genetic alterations and the tumour immune microenvironment. Strategies to enhance anti-tumour immunity have been investigated in ovarian cancer, of which interferon activating therapies present as an attractive option. Of the several type I interferon (IFN-1) stimulating therapies, exogenously activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is emerging as a promising avenue. Herein, we highlight our current understanding of how constitutive and induced cGAS-STING pathway activation influences the ovarian tumour microenvironment. We further elaborate on the links between the genomic alterations prevalent in ovarian tumours and how the resultant immune phenotypes can make them more susceptible to exogenous STING pathway activation and potentiate immune-mediated killing of cancer cells. The therapeutic potential of cGAS-STING pathway activation in ovarian cancer and factors implicating treatment outcomes are discussed, providing a rationale for future combinatorial treatment approaches on the backbone of chemotherapy.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49.
Wilky BA. Immune checkpoint inhibitors: The linchpins of modern immunotherapy. Immunol Rev. 2019;290:6–23.
Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79:4557–66.
Trujillo JA, Sweis RF, Bao R, Luke JJT. Cell-inflamed versus Non-T cell-inflamed tumors: A conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol Res. 2018;6:990–1000.
Borden EC. Interferons alpha and beta in cancer: Therapeutic opportunities from new insights. Nat Rev Drug Disco. 2019;18:219–34.
Kwon J, Bakhoum SF. The cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 2020;10:26–39.
Berger G, Marloye M, Lawler SE. Pharmacological modulation of the STING pathway for cancer immunotherapy. Trends Mol Med. 2019;25:412–27.
Atianand MK, Fitzgerald KA. Molecular basis of DNA recognition in the immune system. J Immunol. 2013;190:1911–8.
Yu L, Liu P. Cytosolic DNA sensing by cGAS: Regulation, function, and human diseases. Signal Transduct Target Ther. 2021;6:170.
Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 2013;339:786–91.
Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20:657–74.
Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21:501–21.
Li X, Zhu Y, Zhang X, An X, Weng M, Shi J, et al. An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP. J Clin Invest. 2021;132:1–11.
Wu J, Sun L, Chen X, Du F, Shi H, Chen C, et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 2013;339:826–30.
Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 2008;455:674–8.
Zhang C, Shang G, Gui X, Zhang X, Bai XC, Chen ZJ. Structural basis of STING binding with and phosphorylation by TBK1. Nature 2019;567:394–8.
Vashi N, Bakhoum SF. The evolution of STING signaling and its involvement in cancer. Trends Biochem Sci. 2021;46:446–60.
Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1. J Virol. 2014;88:5328–41.
Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 2018;553:467–72.
Van Eyndhoven LC, Singh A, Tel J. Decoding the dynamics of multilayered stochastic antiviral IFN-I responses. Trends Immunol. 2021.
Bai L, Li W, Zheng W, Xu D, Chen N, Cui J. Promising targets based on pattern recognition receptors for cancer immunotherapy. Pharm Res. 2020;159:105017.
Ghaffari A, Peterson N, Khalaj K, Vitkin N, Robinson A, Francis JA, 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;119:440–9.
Marcus A, Mao AJ, Lensink-Vasan M, Wang L, Vance RE, Raulet DH. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 2018;49:754–63. e4.
Armstrong DK, Alvarez RD, Bakkum-Gamez JN, Barroilhet L, Behbakht K, Berchuck A, et al. Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19:191–226.
Zhang S, Dolgalev I, Zhang T, Ran H, Levine DA, Neel BG. Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma. Nat Commun. 2019;10:5367.
Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet 2019;393:1240–53.
Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC Jr., Beral V, et al. Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15:668–79.
Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015;521:489–94.
Jimenez-Sanchez A, Memon D, Pourpe S, Veeraraghavan H, Li Y, Vargas HA, et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 2017;170:927–38. e20.
Stack MS, Nephew KP, Burdette JE, A KM. The tumor microenvironment of high grade serous ovarian cancer. Cancers (Basel). 2018;11:21.
Zhang AW, McPherson A, Milne K, Kroeger DR, Hamilton PT, Miranda A, et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell 2018;173:1755–69. e22.
Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 1978;38:2651–60.
Westergaard MCW, Milne K, Pedersen M, Hasselager T, Olsen LR, Anglesio MS, et al. Changes in the tumor immune microenvironment during disease progression in patients with ovarian cancer. Cancers (Basel). 2020;12:3828.
Lo CS, Sanii S, Kroeger DR, Milne K, Talhouk A, Chiu DS, et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clin Cancer Res. 2017;23:925–34.
Ovarian Tumor Tissue Analysis C, Goode EL, Block MS, Kalli KR, Vierkant RA, Chen W, et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 2017;3:e173290.
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.
Santoiemma PP, Powell DJ Jr. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol Ther. 2015;16:807–20.
Wouters MC, Komdeur FL, Workel HH, Klip HG, Plat A, Kooi NM, et al. Treatment regimen, surgical outcome, and T-cell differentiation influence prognostic benefit of tumor-infiltrating lymphocytes in high-grade serous ovarian cancer. Clin Cancer Res. 2016;22:714–24.
Amobi A, Qian F, Lugade AA, Odunsi K. Tryptophan catabolism and cancer immunotherapy targeting IDO mediated immune suppression. Adv Exp Med Biol. 2017;1036:129–44.
Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, et al. Phase I study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in advanced solid tumors. Clin Cancer Res. 2019;25:3220–8.
Yang K, Zhao W, Lou G, Rong Z, Xu H, Wang W, et al. An immunophenotyping of ovarian cancer with clinical and immunological significance. Front Immunol. 2018;9:757.
Gaillard SL, Secord AA, Monk B. The role of immune checkpoint inhibition in the treatment of ovarian cancer. Gynecol Oncol Res Pr. 2016;3:11.
Kristeleit R, Davidenko I, Shirinkin V, El-Khouly F, Bondarenko I, Goodheart MJ, et al. A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer. Gynecol Oncol. 2017;146:484–90.
Hornburg M, Desbois M, Lu S, Guan Y, Lo AA, Kaufman S, et al. Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer. Cancer Cell. 2021;39:928–44. e6.
Au KK, Le Page C, Ren R, Meunier L, Clement I, Tyrishkin K, et al. STAT1-associated intratumoural TH1 immunity predicts chemotherapy resistance in high-grade serous ovarian cancer. J Pathol Clin Res. 2016;2:259–70.
Nersesian S, Schwartz SL, Grantham SR, MacLean LK, Lee SN, Pugh-Toole M, et al. NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis. Transl Oncol. 2021;14:100930.
Henriksen JR, Donskov F, Waldstrom M, Jakobsen A, Hjortkjaer M, Petersen CB, et al. Favorable prognostic impact of Natural Killer cells and T cells in high-grade serous ovarian carcinoma. Acta Oncol. 2020;59:652–9.
Truxova I, Kasikova L, Hensler M, Skapa P, Laco J, Pecen L, et al. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients. J Immunother Cancer. 2018;6:139.
Noy R, Pollard JW. Tumor-associated macrophages: From mechanisms to therapy. Immunity 2014;41:49–61.
Liu R, Hu R, Zeng Y, Zhang W, Zhou HH. Tumour immune cell infiltration and survival after platinum-based chemotherapy in high-grade serous ovarian cancer subtypes: A gene expression-based computational study. EBioMedicine. 2020;51:102602.
Gao Y, Chen L, Cai G, Xiong X, Wu Y, Ma D, et al. Heterogeneity of immune microenvironment in ovarian cancer and its clinical significance: A retrospective study. Oncoimmunology 2020;9:1760067.
Etzerodt A, Moulin M, Doktor TK, Delfini M, Mossadegh-Keller N, Bajenoff M, et al. Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer. J Exp Med. 2020;217.
Mlynska A, Povilaityte E, Zemleckaite I, Zilionyte K, Strioga M, Krasko J, et al. Platinum sensitivity of ovarian cancer cells does not influence their ability to induce M2-type macrophage polarization. Am J Reprod Immunol. 2018;80:e12996.
Baert T, Vankerckhoven A, Riva M, Van Hoylandt A, Thirion G, Holger G, et al. Myeloid derived suppressor cells: Key drivers of immunosuppression in ovarian cancer. Front Immunol. 2019;10:1273.
Pepin G, Gantier MP. cGAS-STING activation in the tumor microenvironment and its role in cancer immunity. Adv Exp Med Biol. 2017;1024:175–94.
Pu F, Chen F, Liu J, Zhang Z, Shao Z. Immune regulation of the cGAS-STING signaling pathway in the tumor microenvironment and its clinical application. Onco Targets Ther. 2021;14:1501–16.
de Queiroz N, Xia T, Konno H, Barber GN. Ovarian cancer cells commonly exhibit defective STING signaling which affects sensitivity to viral oncolysis. Mol Cancer Res. 2019;17:974–86.
Woo SR, Corrales L, Gajewski TF. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 2015;36:250–6.
Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014;41:830–42.
Li W, Lu L, Lu J, Wang X, Yang C, Jin J, et al. cGAS-STING-mediated DNA sensing maintains CD8(+) T cell stemness and promotes antitumor T cell therapy. Sci Transl Med. 2020;12;eaay9013.
Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3’-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014;9:e99988.
Miao L, Qi J, Zhao Q, Wu QN, Wei DL, Wei XL, et al. Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells. Theranostics 2020;10:498–515.
Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 2014;41:843–52.
Shen J, Zhao W, Ju Z, Wang L, Peng Y, Labrie M, et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2019;79:311–9.
Lee EK, Konstantinopoulos PA. Combined PARP and immune checkpoint inhibition in ovarian Cancer. Trends Cancer 2019;5:524–8.
Galluzzi L, Humeau J, Buque A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–41.
Hong C, Tijhuis AE, Foijer F. The cGAS Paradox: Contrasting roles for cGAS-STING pathway in chromosomal instability. Cells. 2019;8:1228.
Jimenez-Sanchez A, Cybulska P, Mager KL, Koplev S, Cast O, Couturier DL, et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat Genet. 2020;52:582–93.
Konno H, Yamauchi S, Berglund A, Putney RM, Mule JJ, Barber GN. Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production. Oncogene 2018;37:2037–51.
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;14:282–97.
Zhang J, Chen Y, Chen X, Zhang W, Zhao L, Weng L, et al. Deubiquitinase USP35 restrains STING-mediated interferon signaling in ovarian cancer. Cell Death Differ. 2021;28:139–55.
McLaughlin LJ, Stojanovic L, Kogan AA, Rutherford JL, Choi EY, Yen RC, et al. Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency. Proc Natl Acad Sci USA. 2020;117:17785–95.
Yi G, Brendel VP, Shu C, Li P, Palanathan S, Cheng Kao C. Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides. PLoS One. 2013;8:e77846.
Patel S, Blaauboer SM, Tucker HR, Mansouri S, Ruiz-Moreno JS, Hamann L, et al. The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele. J Immunol. 2017;198:776–87.
Nersesian S, Glazebrook H, Toulany J, Grantham SR, Boudreau JE. Naturally killing the silent killer: NK cell-based immunotherapy for ovarian cancer. Front Immunol. 2019;10:1782.
Le Bert N, Lam AR, Ho SS, Shen YJ, Liu MM, Gasser S. STING-dependent cytosolic DNA sensor pathways regulate NKG2D ligand expression. Oncoimmunology 2014;3:e29259.
Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: A novel biomarker in cancer detection. Cell Res. 2014;24:766–9.
Kitai Y, Kawasaki T, Sueyoshi T, Kobiyama K, Ishii KJ, Zou J, et al. DNA-containing exosomes derived from cancer cells treated with topotecan activate a STING-dependent pathway and reinforce antitumor immunity. J Immunol. 2017;198:1649–59.
Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS One. 2010;5:e11469.
Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36–49.
Hartlova A, Erttmann SF, Raffi FA, Schmalz AM, Resch U, Anugula S, et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 2015;42:332–43.
McCormick A, Donoghue P, Dixon M, O’Sullivan R, O’Donnell RL, Murray J, et al. Ovarian cancers harbor defects in nonhomologous end joining resulting in resistance to rucaparib. Clin Cancer Res. 2017;23:2050–60.
Tsibulak I, Wieser V, Degasper C, Shivalingaiah G, Wenzel S, Sprung S, et al. BRCA1 and BRCA2 mRNA-expression prove to be of clinical impact in ovarian cancer. Br J Cancer. 2018;119:683–92.
Huang YW. Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis. Med (Baltim). 2018;97:e9380.
Hu M, Zhou M, Bao X, Pan D, Jiao M, Liu X, et al. ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation. J Clin Invest. 2021;131:e139333.
Mowat C, Mosley SR, Namdar A, Schiller D, Baker K. Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN-driven CCL5 and CXCL10. J Exp Med. 2021;218: e139333.
Reislander T, Groelly FJ, Tarsounas M. DNA Damage and Cancer Immunotherapy: A STING in the Tale. Mol Cell. 2020;80:21–8.
Parkes EE, Walker SM, Taggart LE, McCabe N, Knight LA, Wilkinson R, et al. Activation of STING-dependent innate immune signaling by S-phase-specific DNA damage in breast cancer. J Natl Cancer Inst. 2017;109:djw199.
Kepp O, Galluzzi L, Martins I, Schlemmer F, Adjemian S, Michaud M, et al. Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. Cancer Metastasis Rev. 2011;30:61–9.
Petroni G, Buque A, Zitvogel L, Kroemer G, Galluzzi L. Immunomodulation by targeted anticancer agents. Cancer Cell. 2021;39:310–45.
Bruand M, Barras D, Mina M, Ghisoni E, Morotti M, Lanitis E, et al. Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING. Cell Rep. 2021;36:109412.
Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl J Med. 2019;381:2391–402.
Liu MC, Sutedja J, Tewari KS. Niraparib in the maintenance treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Safety and efficacy. Expert Rev Anticancer Ther. 2021;21:475–80.
Ding L, Kim HJ, Wang Q, Kearns M, Jiang T, Ohlson CE, et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 2018;25:2972–80. e5.
Grabosch S, Bulatovic M, Zeng F, Ma T, Zhang L, Ross M, et al. Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene 2019;38:2380–93.
Lampert EJ, Cimino-Mathews A, Lee JS, Nair J, Lee MJ, Yuno A, et al. Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses. J Immunother Cancer. 2020;8:e000516.
Shakfa N, Siemens DR, Koti M. Revisiting immunogenic cell death to improve treatment response in cancer. Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance 2021. p. 65–90.
Wilkinson RDA, McCabe, N Parkes, EE, Barros, EM, Johnston, DI, Ali, RMM, et al. Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation. bioRxiv. 2019. https://doi.org/10.1101/764662.
This work was supported by funding from the Canadian Institutes for Health Research and the Ontario Ministry of Research, Innovation, and Science Early Researcher Award to MK. Fellowship support to NS was provided by the Franklin Bracken Fellowship, Queen’s University, and the Canada Graduate Scholarship program.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Shakfa, N., Li, D., Nersesian, S. et al. The STING pathway: Therapeutic vulnerabilities in ovarian cancer. Br J Cancer 127, 603–611 (2022). https://doi.org/10.1038/s41416-022-01797-4