Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

01-12-2020 | Interferon | Review

cGAS-STING, an important pathway in cancer immunotherapy

Authors: Minlin Jiang, Peixin Chen, Lei Wang, Wei Li, Bin Chen, Yu Liu, Hao Wang, Sha Zhao, Lingyun Ye, Yayi He, Caicun Zhou

Published in: Journal of Hematology & Oncology | Issue 1/2020

Login to get access

Abstract

Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. Multiple STING agonists were developed for cancer therapy study with great results achieved in pre-clinical work. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising role for cancer immunotherapy. STING agonists co-administrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Despite the applications of STING agonists in cancer immunotherapy, lots of obstacles remain for further study. In this review, we mainly examine the biological characters, current applications, challenges, and future directions of cGAS-STING in cancer immunotherapy.
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRefPubMed
2.
Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9–16.PubMedPubMedCentral
3.
Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.PubMedPubMedCentral
4.
Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling (vol 455, pg 674, 2008). Nature. 2008;456(7219):274.
5.
6.
Berger G, Marloye M, Lawler SE. Pharmacological modulation of the STING pathway for cancer immunotherapy. Trends Mol Med. 2019;25(5):412–27.PubMed
7.
Kwon J, Bakhoum SF. The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2020;10(1):26–39.PubMed
8.
Burdette DL, Vance RE. STING and the innate immune response to nucleic acids in the cytosol. Nature Immunology. 2013;14(1):19–26.PubMed
9.
Dhanwani R, Takahashi M, Sharma S. Cytosolic sensing of immuno-stimulatory DNA, the enemy within. Curr Opin Immunol. 2018;50:82–7.PubMed
10.
Chen Q, Sun LJ, Chen ZJJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016;17(10):1142–9.PubMed
11.
West AP, Khoury-Hanold W, Staron M, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553.PubMedPubMedCentral
12.
Civril F, Deimling T, Mann CCD, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498(7454):332.PubMedPubMedCentral
13.
Sun LJ, Wu JX, Du FH, Chen X, Chen ZJJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339(6121):786–91.PubMed
14.
Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498(7454):380.PubMedPubMedCentral
15.
Shang GJ, Zhang CG, Chen ZJJ, Bai XC, Zhang XW. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature. 2019;567(7748):389.PubMedPubMedCentral
16.
Zhang CG, Shang GJ, Gui X, Zhang XW, Bai XC, Chen ZJJ. Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019;567(7748):394.PubMedPubMedCentral
17.
Gao P, Ascano M, Zillinger T, et al. Structure-function analysis of STING activation by c[G(2',5') pA(3',5')p] and targeting by antiviral DMXAA. Cell. 2013;154(4):748–62.PubMedPubMedCentral
18.
Diner EJ, Burdette DL, Wilson SC, et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Reports. 2013;3(5):1355–61.PubMed
19.
Xia TL, Konno H, Barber GN. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Res. 2016;76(22):6747–59.PubMed
20.
Xia TL, 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):282–97.PubMed
21.
Kitapma S, Ivanova E, Guo S, et al. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov. 2019;9(1):34–45.
22.
Tan YS, Sansanaphongpricha K, Xie YY, et al. Mitigating SOX2-potentiated immune escape of head and neck squamous cell carcinoma with a STING-inducing nanosatellite vaccine. Clin Cancer Res. 2018;24(17):4242–55.PubMedPubMedCentral
23.
Li A, Yi M, Qin S, Song Y, Chu Q, Wu K. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy. J Hematol Oncol. 2019;12(1):35.
24.
Harlin H, Meng Y, Peterson AC, et al. Chemokine expression in melanoma metastases associated with CD8(+) T-cell recruitment. Cancer Res. 2009;69(7):3077–85.PubMed
25.
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(4):754.PubMedPubMedCentral
26.
Dou ZX, Ghosh K, Vizioli MG, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550(7676):402–6.PubMedPubMedCentral
27.
Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. Plos Biol. 2008;6(12):2853–68.PubMed
28.
Yang H, Wang HZ, Ren JY, Chen Q, Chen ZJJ. cGAS is essential for cellular senescence. Proc Natl Acad Sci USA. 2017;114(23):E4612–20.PubMedPubMedCentral
29.
Gluck S, Guey B, Gulen MF, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017;19(9):1061.PubMedPubMedCentral
30.
Ranoa DRE, Widau RC, Mallon S, et al. STING promotes homeostasis via regulation of cell proliferation and chromosomal stability. Cancer Res. 2019;79(7):1465–79.PubMed
31.
Woo SR, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–42.PubMedPubMedCentral
32.
Fuertes MB, Woo SR, Burnett B, Fu YX, Gajewski TF. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 2013;34(2):67–73.PubMed
33.
Liu HP, Zhang HP, Wu XY, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature. 2018;563(7729):131.PubMed
34.
Parlato S, Santini SM, Lapenta C, et al. Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood. 2001;98(10):3022–9.PubMed
35.
Bertucci F, Ueno NT, Finetti P, et al. Gene expression profiles of inflammatory breast cancer: correlation with response to neoadjuvant chemotherapy and metastasis-free survival. Ann Oncol. 2014;25(2):358–65.PubMed
36.
Fuertes MB, Kacha AK, Kline J, et al. Host type I IFN signals are required for antitumor CD8(+) T cell responses through CD8 alpha(+) dendritic cells. J Exp Med. 2011;208(10):2005–16.PubMedPubMedCentral
37.
Diamond MS, Kinder M, Matsushita H, et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 2011;208(10):1989–2003.PubMedPubMedCentral
38.
Ager CR, Reilley MJ, Nicholas C, Bartkowiak T, Jaiswal AR, Curran MA. Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity. Cancer Immunol Res. 2017;5(8):676–84.PubMedPubMedCentral
39.
Tang CHA, Zundell JA, Ranatunga S, et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells. Cancer Res. 2016;76(8):2137–52.PubMedPubMedCentral
40.
Demaria O, De Gassart A, Coso S, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci USA. 2015;112(50):15408–13.PubMedPubMedCentral
41.
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):1018–30.PubMedPubMedCentral
42.
McKeage MJ, Reck M, Jameson MB, et al. Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800 mg/m(2) combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer. Lung Cancer. 2009;65(2):192–7.PubMed
43.
Ramanjulu JM, Pesiridis GS, Yang J, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature. 2018;564(7736):439–43.PubMed
44.
Karaolis DKR, Cheng KR, Lipsky M, et al. 3 ',5 '-Cyclic diguanylic acid (c-di-GMP) inhibits basal and growth factor-stimulated human colon cancer cell proliferation. Biochem Biophys Res Commun. 2005;329(1):40–5.PubMed
45.
Li T, Cheng H, Yuan H, et al. Antitumor activity of cGAMP via stimulation of cGAS-cGAMP-STING-IRF3 mediated innate immune response. Sci Rep. 2016;6:19049.PubMedPubMedCentral
46.
Shae D, Becker KW, Christov P, et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nat Nanotechnol. 2019;14(3):269.PubMedPubMedCentral
47.
Berry S, Giraldo N, Nguyen P, et al. Correction to: 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018). J Immunother Cancer. 2019;7(1):46.PubMedPubMedCentral
48.
Mukai K, Konno H, Akiba T, Uemura T, Waguri S, Kobayashi T, Barber GN, Arai H, Taguchi T. Activation of STING requires palmitoylation at the Golgi. Nat Commun. 2016;7:11932.
49.
Lara PN, Douillard JY, Nakagawa K, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(22):2965–71.PubMed
50.
Conlon J, Burdette DL, Sharma S, et al. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol. 2013;190(10):5216–25.PubMed
51.
Dubensky TW, Reed SG. Adjuvants for cancer vaccines. Semin Immunol. 2010;22(3):155–61.PubMed
52.
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.
53.
Kinkead HL, Hopkins A, Lutz E, et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. Jci Insight. 2018;3(20):e122857.
54.
Wang ZL, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol Immunother. 2015;64(8):1057–66.PubMedPubMedCentral
55.
Miao L, Li LX, Huang YX, et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat Biotechnol. 2019;37(10):1174.PubMed
56.
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.PubMed
57.
Grabosch S, Bulatovic M, Zeng FTZ, et al. Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene. 2019;38(13):2380–93.PubMed
58.
59.
Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Reenberg RAG. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548(7668):466.PubMedPubMedCentral
60.
Wilson DR, Sen R, Sunshine JC, Pardoll DM, Green JJ, Kim YJ. Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. Nanomed Nanotechnol Biol Med. 2018;14(2):237–46.
61.
Twumasi-Boateng K, Pettigrew JL, Kwok YYE, Bell JC, Nelson BH. Oncolytic viruses as engineering platforms for combination immunotherapy (vol 18, pg 419, 2018). Nat Rev Cancer. 2018;18(8):526.PubMed
62.
Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–U98.PubMed
63.
de Queiroz NMGP, Xia TL, Konno H, Barber GN. Ovarian cancer cells commonly exhibit defective STING signaling which affects sensitivity to viral oncolysis. Mol Cancer Res. 2019;17(4):974–86.PubMed
64.
Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma-subunit or zeta-subunit of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA. 1993;90(2):720–4.PubMedPubMedCentral
65.
Pang YY, Hou XY, Yang CS, Liu YQ, Jiang G. Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy. Mol Cancer. 2018;17(1):91.
66.
Newick K, O'Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med. 2017;68:139–52.PubMed
67.
Zhang EH, Gu JY, Xu HM. Prospects for chimeric antigen receptor-modified T cell therapy for solid tumors. Mol Cancer. 2018;17(1):7.
68.
Smith TT, Moffett HF, Stephan SB, et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. Journal of Clinical Investigation. 2017;127(6):2176–91.PubMedPubMedCentral
69.
Chen Q, Boire A, Jin X, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533(7604):493.PubMedPubMedCentral
70.
Ding L, Huang XF, Dong GJ, et al. Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal. Biochim Biophys Acta-Mol Basis Dis. 2015;1852(11):2494–503.
71.
Lemos H, Mohamed E, Huang L, et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 2016;76(8):2076–81.PubMedPubMedCentral
72.
Song SS, Peng PK, Tang ZQ, et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci Rep. 2017;7:39858.
73.
Toso A, Revandkar A, Di Mitri D, et al. Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 2014;9(1):75–89.PubMed
74.
Bakhoum SF, Ngo B, Laughney AM, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018;553(7689):467.PubMedPubMedCentral
75.
Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37(3):193–207.PubMedPubMedCentral
76.
Gulen MF, Koch U, Haag SM, et al. Signalling strength determines proapoptotic functions of STING. Nat Commun. 2017;8(1):427.PubMedPubMedCentral
77.
Song M, Sandoval TA, Chae CS, et al. IRE1alpha-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature. 2018;562(7727):423–8.PubMedPubMedCentral
78.
Pommier A, Anaparthy N, Memos N, et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science. 2018;360(6394):1202.
79.
Terai H, Kitajima S, Potter DS, et al. ER stress signaling promotes the survival of cancer “persister cells” tolerant to EGFR tyrosine kinase inhibitors. Cancer Res. 2018;78(4):1044–57.PubMed
80.
Harrington KJ, Brody J, Ingham M, et al. Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas. Ann Oncol. 2018;29:712.
81.
An X, Zhu YY, Zheng TS, et al. An analysis of the expression and association with immune cell infiltration of the cGAS/STING pathway in pan-cancer. Mol Ther Nucleic Acids. 2019;14:80–9.PubMed
82.
Corrales L, Woo SR, Williams JB, McWhirter SM, Dubensky TW, Gajewski TF. Antagonism of the STING pathway via activation of the AIM2 inflammasome by intracellular DNA. J Immunol. 2016;196(7):3191–8.PubMed
83.
Flood BA, Higgs EF, Li SY, Luke JJ, Gajewski TF. STING pathway agonism as a cancer therapeutic. Immunol Rev. 2019;290(1):24–38.PubMedPubMedCentral
84.
Srikanth S, Woo JS, Wu BB, et al. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat Immunol. 2019;20(2):152.PubMedPubMedCentral
85.
Haag SM, Gulen MF, Reymond L, et al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018;559(7713):269–73.PubMed
86.
Yang XM, Zhang XM, Fu ML, et al. Targeting the tumor microenvironment with interferon-beta bridges innate and adaptive immune responses. Cancer Cell. 2014;25(1):37–48.PubMedPubMedCentral
87.
Sivick KE, Desbien AL, Glickman LH, et al. Magnitude of therapeutic STING activation determines CD8(+) T cell-mediated anti-tumor immunity. Cell Rep. 2018;25(11):3074.PubMed
Metadata
Title
cGAS-STING, an important pathway in cancer immunotherapy
Authors
Minlin Jiang
Peixin Chen
Lei Wang
Wei Li
Bin Chen
Yu Liu
Hao Wang
Sha Zhao
Lingyun Ye
Yayi He
Caicun Zhou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00916-z

Other articles of this Issue 1/2020

Journal of Hematology & Oncology 1/2020 Go to the issue

Rapid communication

First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer

Research

Oct4 promotes M2 macrophage polarization through upregulation of macrophage colony-stimulating factor in lung cancer

Rapid communication

Pre-transplant MRD negativity predicts favorable outcomes of CAR-T therapy followed by haploidentical HSCT for relapsed/refractory acute lymphoblastic leukemia: a multi-center retrospective study

Review

Emerging therapies in mantle cell lymphoma

Review

Immunosenescence: a key player in cancer development

Letter to the Editor

Axicabtagene ciloleucel CD19 CAR-T cell therapy results in high rates of systemic and neurologic remissions in ten patients with refractory large B cell lymphoma including two with HIV and viral hepatitis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits