Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

cGAS and cancer therapy: a double-edged sword

Abstract

Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The human cGAS protein structure.
Fig. 2: The cGAS-STING signaling pathway.
Fig. 3: The antitumor functions of cGAS-STING.
Fig. 4: The tumor-promoting roles of cGAS–STING.

References

  1. Aravind L, Koonin EV. DNA polymerase beta-like nucleotidyltransferase superfamily: identification of three new families, classification and evolutionary history. Nucleic Acids Res. 1999;27:1609–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sun LJ, Wu JX, Du FH, 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.

    Article  CAS  PubMed  Google Scholar 

  3. Li S, Hong Z, Wang Z, Li F, Mei J, Huang L, et al. The cyclopeptide astin C specifically inhibits the innate immune CDN sensor STING. Cell Rep. 2018;25:3405–21.

    Article  CAS  PubMed  Google Scholar 

  4. Nunes SC. Tumor microenvironment - selective pressures boosting cancer progression. Adv Exp Med Biol. 2020;1219:35–49.

    Article  CAS  PubMed  Google Scholar 

  5. Liu H, Zhang H, Wu X, Ma D, Wu J, Wang L, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature. 2018;563:131–6.

    Article  CAS  PubMed  Google Scholar 

  6. Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533:493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schadt L, Sparano C, Schweiger NA, Silina K, Cecconi V, Lucchiari G, et al. Cancer-cell-intrinsic cGAS expression mediates tumor immunogenicity. Cell Rep. 2019;29:1236–48.

    Article  CAS  PubMed  Google Scholar 

  8. Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498:332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kuchta K, Knizewski L, Wyrwicz LS, Rychlewski L, Ginalski K. Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human. Nucleic Acids Res. 2009;37:7701–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X, Conrad C, et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science. 2015;349:1232–6.

    Article  CAS  PubMed  Google Scholar 

  11. Kranzusch PJ, Lee ASY, Berger JM, Doudna JA. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep. 2013;3:1362–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhou W, Whiteley AT, de Oliveira Mann CC, Morehouse BR, Nowak RP, Fischer ES, et al. Structure of the human cGASDNA complex reveals enhanced control of immune surveillance. Cell. 2018;174:300–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang X, Wu J, Du F, Xu H, Sun L, Chen Z, et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 2014;6:421–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Du M, Chen ZJ. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science. 2018;361:704–9.

    Article  CAS  PubMed  Google Scholar 

  15. Wu JX, 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.

    Article  CAS  PubMed  Google Scholar 

  16. Fenech M, Kirsch-Volders M, Natarajan AT, Surralles J, Crott JW, Parry J, et al. Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis. 2011;26:125–32.

    Article  CAS  PubMed  Google Scholar 

  17. Rodero MP, Tesser A, Bartok E, Rice GI, Della Mina E, Depp M, et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat Commun. 2017;8:2176.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dobbs N, Burnaevskiy N, Chen D, Gonugunta VK, Alto NM, Yan N, et al. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe. 2015;18:157–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal. 2012;5:ra20.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003;4:491–6.

  22. Sharma S, TenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science. 2003;300:1148–51.

    Article  CAS  PubMed  Google Scholar 

  23. Hong C, Tijhuis AE, Foijer F. The cGAS paradox: contrasting roles for cGAS-STING pathway in chromosomal instability. Cells. 2019;8:1228.

    Article  CAS  PubMed Central  Google Scholar 

  24. Chen H, Chen H, Zhang J, Wang Y, Simoneau A, Yang H, et al. cGAS suppresses genomic instability as a decelerator of replication forks. Sci Adv. 2020;6:eabb8941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Basit A, Cho MG, Kim EY, Kwon D, Kang SJ, Lee JH. The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels. Exp Mol Med. 2020;52:643–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Seo GJ, Yang A, Tan B, Kim S, Liang Q, Choi Y, et al. Akt kinase-mediated checkpoint of cGAS DNA sensing pathway. Cell Rep. 2015;13:440–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, et al. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol. 2016;17:369–78.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang J, Zhao J, Xu S, Li J, He S, Zeng Y, et al. Species-specific deamidation of cGAS by herpes simplex virus UL37 protein facilitates viral replication. Cell Host Microbe. 2018;24:234–248 e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hu MM, Yang Q, Xie XQ, Liao CY, Lin H, Liu TT, et al. Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor STING to regulate the kinetics of response to DNA virus. Immunity. 2016;45:555–69.

    Article  CAS  PubMed  Google Scholar 

  31. Wang Q, Huang L, Hong Z, Lv Z, Mao Z, Tang Y, et al. The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response. PLoS Pathog. 2017;13:e1006264.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Dai J, Huang YJ, He X, Zhao M, Wang X, Liu ZS, et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell. 2019;176:1447–60 e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bakhoum SF, Landau DA. Chromosomal instability as a driver of tumor heterogeneity and evolution. Cold Spring Harb Perspect Med. 2017;7:a029611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu MM, Pu Y, Han D, Shi Y, Cao X, Liang H, et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein alpha signaling. Immunity. 2017;47:363–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fuertes MB, Woo SR, Burnett B, Fu YX, Gajewski TF. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 2013;34:67–73.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ, et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013;341:1390–4.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Paglialunga L, Salih Z, Ricciuti B, Califano R. Immune checkpoint blockade in small cell lung cancer: is there a light at the end of the tunnel? ESMO Open. 2016;1:e000022.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wang H, Hu S, Chen X, Shi H, Chen C, Sun L, et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc Natl Acad Sci USA. 2017;114:1637–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu MZ, Cheng WC, Chen SF, Nieh S, O’Connor C, Liu CL, et al. miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nat Cell Biol. 2017;19:1286–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Campisi J, di Fagagna FD. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40.

    Article  CAS  PubMed  Google Scholar 

  45. Wolter K, Zender L. Therapy-induced senescence - an induced synthetic lethality in liver cancer? Nat Rev Gastroenterol Hepatol. 2020;17:135–36.

    Article  PubMed  Google Scholar 

  46. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602.

    Article  CAS  PubMed  Google Scholar 

  47. Glück S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat cell Biol. 2017;19:1061–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Yang H, Wang H, Ren J, Chen Q, Chen ZJ. cGAS is essential for cellular senescence. Proc Natl Acad Sci USA. 2017;114:E4612–E4620.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 2020;34:428–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Katlinskaya YV, Katlinski KV, Yu Q, Ortiz A, Beiting DP, Brice A, et al. Suppression of Type I interferon signaling overcomes oncogene-induced senescence and mediates melanoma development and progression. Cell Rep. 2016;15:171–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yu Q, Katlinskaya YV, Carbone CJ, Zhao B, Katlinski KV, Zheng H, et al. DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep. 2015;11:785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fischer TD, Wang C, Padman BS, Lazarou M, Youle RJ. STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain. J Cell Biol. 2020;219:e202009128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Liu D, Wu H, Wang C, Li Y, Tian H, Siraj S, et al. STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2019;26:1735–49.

    Article  CAS  PubMed  Google Scholar 

  55. Thomsen MK, Skouboe MK, Boularan C, Vernejoul F, Lioux T, Leknes SL, et al. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. Oncogene. 2020;39:1652–64.

    Article  CAS  PubMed  Google Scholar 

  56. Liang QM, Seo GJ, Choi YJ, Kwak MJ, Ge J, Rodgers MA, et al. Crosstalk between the cGAS DNA Sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe. 2014;15:228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zierhut C, Yamaguchi N, Paredes M, Luo JD, Carroll T, Funabiki H, et al. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell. 2019;178:302–315 e23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li C, Liu W, Wang F, Hayashi T, Mizuno K, Hattori S, et al. DNA damage-triggered activation of cGAS-STING pathway induces apoptosis in human keratinocyte HaCaT cells. Mol Immunol. 2021;131:180–90.

    Article  CAS  PubMed  Google Scholar 

  59. Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci USA. 2013;110:16544–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xia T, Konno H, Barber GN. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Res. 2016;76:6747–59.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. Bu Y, Liu F, Jia QA, Yu SN. Decreased expression of TMEM173 predicts poor prognosis in patients with hepatocellular carcinoma. PLoS One. 2016;11:e0165681.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Song S, Peng P, Tang Z, Zhao J, Wu W, Li H, et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci Rep. 2017;7:39858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Raaby Gammelgaard K, Sandfeld-Paulsen B, Godsk SH, Demuth C, Meldgaard P, Sorensen BS, et al. cGAS-STING pathway expression as a prognostic tool in NSCLC. Transl Lung Cancer Res. 2021;10:340–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.

    Article  CAS  PubMed  Google Scholar 

  66. Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:1–9.

    Google Scholar 

  67. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005;11:1314–21.

    Article  CAS  PubMed  Google Scholar 

  68. Liang H, Deng L, Hou Y, Meng X, Huang X, Rao E, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun. 2017;8:1736.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, Arbab AS, et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 2016;76:2076–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tegowski M, Baldwin A. Noncanonical NF-kappaB in cancer. Biomedicines. 2018;6:66.

    Article  PubMed Central  CAS  Google Scholar 

  71. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Coppe JP, Patil CK, Rodier F, Sun YU, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.

    Article  CAS  PubMed  Google Scholar 

  73. Nadeem MS, Kumar V, Al-Abbasi FA, Kamal MA, Anwar F. Risk of colorectal cancer in inflammatory bowel diseases. Semin Cancer Biol. 2020;64:51–60.

    Article  PubMed  Google Scholar 

  74. Freeman HJ. Colorectal cancer risk in Crohn’s disease. World J Gastroenterol. 2008;14:1810–1.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jiang H, Xue X, Panda S, Kawale A, Hooy RM, Liang F, et al. Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. Embo J. 2019;38:e102718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ceccaldi R, Rondinelli B, D’Andrea AD. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 2016;26:52–64.

    Article  CAS  PubMed  Google Scholar 

  78. Murga M, Jaco I, Fan Y, Soria R, Martinez-Pastor B, Cuadrado M, et al. Global chromatin compaction limits the strength of the DNA damage response. J Cell Biol. 2007;178:1101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hengel SR, Spies MA, Spies M. Small-molecule inhibitors targeting DNA repair and DNA repair deficiency in research and cancer therapy. Cell Chem Biol. 2017;24:1101–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pepin G, Gantier MP. cGAS-STING activation in the tumor microenvironment and its role in cancer immunity. Adv Exp Med Biol. 2017;1024:175–194.

    Article  CAS  PubMed  Google Scholar 

  81. Demaria O, De Gassart A, Coso S, Gestermann N, Di Domizio J, Flatz L, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci USA. 2015;112:15408–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li T, Cheng H, Yuan H, Xu Q, Shu C, Zhang Y, et al. Antitumor activity of cGAMP via stimulation of cGAS-cGAMPSTING- IRF3 mediated innate immune response. Sci Rep. 2016;6:19049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chandra D, Quispe-Tintaya W, Jahangir A, Asafu-Adjei D, Ramos I, Sintim HO, et al. STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer. Cancer Immunol Res. 2014;2:901–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tang CH, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells. Cancer Res. 2016;76:2137–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11:1018–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li S, Luo M, Wang Z, Feng Q, Wilhelm J, Wang X, et al. Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat Biomed Eng. 2021;5:455–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yum S, Li MH, Frankel AE, Chen ZJJ. Roles of the cGAS-STING pathway in cancer immunosurveillance and immunotherapy. Annu Rev Cancer Biol. 2019;3:323–44.

    Article  Google Scholar 

  88. Oronsky B, Ray CM, Spira AI, Trepel JB, Carter CA, Cottrill HM. A brief review of the management of platinum-resistantplatinum-refractory ovarian cancer. Med Oncol. 2017;34:103.

    Article  PubMed  CAS  Google Scholar 

  89. 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;119:440–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Baird JR, Friedman D, Cottam B, Dubensky TW, Kanne DB, Bambina S, et al. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors. Cancer Res. 2016;76:50–61.

    Article  CAS  PubMed  Google Scholar 

  91. Lv MZ, Chen M, Zhang R, Zhang W, Wang C, Zhang Y, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020;30:966–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ager CR, Reilley MJ, Nicholas C, Bartkowiak T, Jaiswal AR, Curran MA, et al. Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity. Cancer Immunol Res. 2017;5:676–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, et al. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 2017;8:750.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. An J, Minie M, Sasaki T, Woodward JJ, Elkon KB. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu Rev Med. 2017;68:317–30.

    Article  CAS  PubMed  Google Scholar 

  95. Lee J, Ghonime MG, Wang R, Cassady KA. The antiviral apparatus: STING and oncolytic virus restriction. Mol Ther Oncolytics. 2019;13:7–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer. 2016;4:1–8.

    Article  Google Scholar 

  97. Lopes A, Vandermeulen G, Preat V. Cancer DNA vaccines: current preclinical and clinical developments and future perspectives. J Exp Clin Cancer Res. 2019;38:146.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, Lemmens E, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. 2015;7:283ra52.

    PubMed  PubMed Central  Google Scholar 

  99. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zawit M, Swami U, Awada H, Arnouk J, Milhem M, Zakharia Y, et al. Current status of intralesional agents in treatment of malignant melanoma. Ann Transl Med. 2021;9:1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhu X, Han W, Liu Y, Wang H, Lin D, Fu Z, et al. Rational design of a prodrug to inhibit self-inflammation for cancer treatment. Nanoscale. 2021;13:5817–25.

    Article  CAS  PubMed  Google Scholar 

  102. Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, et al. Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay. PLoS One. 2017;12:e0184843.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Natural Science Foundation of China (81830107) to Qiao-jun He., a grant from the National Natural Science Foundation of China (81773753) to Bo Yang, and a grant from the Natural Science Foundation of Zhejiang Province (LR19H310002) to Hong Zhu. No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

Authors

Contributions

HZ and QL conceived and designed the concept of this review article. QJH and BY amended the manuscript. JMD wrote the manuscript. MJQ, TY, and RHC collected the related research articles and reviews. All authors reviewed and approved the manuscript.

Corresponding authors

Correspondence to Qi Ling or Hong Zhu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Du, Jm., Qian, Mj., Yuan, T. et al. cGAS and cancer therapy: a double-edged sword. Acta Pharmacol Sin 43, 2202–2211 (2022). https://doi.org/10.1038/s41401-021-00839-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-021-00839-6

Keywords

  • cGAS; tumor suppression; tumor promotion; cancer therapy

Search

Quick links