cGAS-STING信号通路在肿瘤治疗中的作用与应用前景

doi:10.3760/cma.j.cn113030-20190509-00170

Abstract
Figure/Table
References()
Related Citation (6)
Read Tracking
Download Tracking

Download: PDF (0 KB) HTML (1 KB)
Export: BibTeX | EndNote (RIS) Supporting Info

Abstract Novel cancer immunotherapy can treat tumors through regulating innate immunity and adaptive immune system. cGMP-AMP synthase (cGAS) is a key regulator of innate immune response to both exogenous and endogenous DNA. After recognizing the cytoplasmic DNA, cGAS produces the second messenger cyclic GMP-AMP (cGAMP), which subsequently combines with the adaptor STING (also known as MITA, MPYS and ERIS) to mediate innate immunity by inducing the production of type I interferons and inflammatory cytokines. Recent studies have revealed that the cGAS/STING signaling pathway can be activated by tumor-derived DNA and by-products of genomic instability and affect the incidence and development of tumors, which plays a critical role in the natural antitumor immunity across cancer types and immune checkpoint blockade therapy. In this article, current understanding of cGAS/STING signaling pathway in tumors was summarized,the pivotal role in tumor immunity and radiotherapy was highlighted, and the potential targeted or alternative therapy of this signaling pathway was reviewed.

	Service

	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	Gao Yanping
	Jiang Xueping
	Liu Xingyu
	Chen Jiarui
	Gong Yan
	Xie Conghua

Key words： cGAS gene STING gene Signaling pathway Neoplasm/radioimmunotherapy

Received: 09 May 2019

Fund:National Natural Science Foundation of China (81572967,81773236);National Project for Improving the Ability of Diagnosis and Treatment of Difficult Diseases, National Key Clinical Speciality Construction Program of China ([2013]544);Health Commission of Hubei Province Scientific Research Project (WJ2019h002)

Corresponding Authors: Xie Conghua, Email:chxie_65@whu.edu.com

Cite this article:

Gao Yanping,Jiang Xueping,Liu Xingyu et al. The role and application prospect of cGAS-STING signaling pathway in tumor treatment[J]. Chinese Journal of Radiation Oncology, 2021, 30(5): 518-522.

URL:

http://journal12.magtechjournal.com/Jweb_fszlx/EN/10.3760/cma.j.cn113030-20190509-00170 OR http://journal12.magtechjournal.com/Jweb_fszlx/EN/Y2021/V30/I5/518

[1] Akira S. Pathogen recognition by innate immunity and its signaling[J]. Proc Jpn Acad Ser B Phys Biol Sci, 2009, 85(4):143-156. DOI:10.2183/pjab.85.143.
[2] Takeuchi O, Akira S. Pattern recognition receptors and inflammation[J]. Cell, 2010, 140(6):805-820. DOI:10.1016/j.cell.2010.01.022.
[3] Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J]. Nature, 2008, 455(7213):674-678. DOI:10.1038/nature07317.
[4] Zhong B, Yang Y, Li S, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation[J]. Immunity, 2008, 29(4):538-550. DOI:10.1016/j.immuni.2008.09.003.
[5] Wu J, Sun L, Chen X, et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA[J]. Science, 2013, 339(6121):826-830. DOI:10.1126/science.1229963.
[6] Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway[J]. Science, 2013, 339(6121):786-791. DOI:10.1126/science.1232458.
[7] Woo SR, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors[J]. Immunity, 2014, 41(5):830-842. DOI:10.1016/j.immuni.2014.10.017.
[8] Mackenzie KJ, Carroll P, Martin CA, et al. cGAS surveillance of micronuclei links genome instability to innate immunity[J]. Nature, 2017, 548(7668):461-465. DOI:10.1038/nature23449.
[9] Harding SM, Benci JL, Irianto J, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei[J]. Nature, 2017, 548(7668):466-470. DOI:10.1038/nature23470.
[10] GLÜck S, Guey B, Gulen MF, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence[J]. Nat Cell Biol, 2017, 19(9):1061-1070. DOI:10.1038/ncb3586.
[11] Dou Z, Ghosh K, Vizioli MG, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer[J]. Nature, 2017, 550(7676):402-406. DOI:10.1038/nature24050.
[12] Wu J, Sun L, Chen X, et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA[J]. Science, 2013, 339(6121):826-830. DOI:10.1126/science.1229963.
[13] Liu S, Cai X, Wu J, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation[J]. Science, 2015, 347(6227):aaa2630. DOI:10.1126/science.aaa2630.
[14] Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer[J]. J Exp Med, 2018, 215(5):1287-1299. DOI:10.1084/jem.20180139.
[15] Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1[J]. J Virol, 2014, 88(10):5328-5341. DOI:10.1128/JVI.00037-14.
[16] Ching LM, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5,6-Dimethylxanthenone-4-acetic acid[J]. Br J Cancer, 2002, 86(12):1937-1942. DOI:10.1038/sj.bjc.6600368.
[17] Roberts ZJ, Ching LM, Vogel SN. IFN-beta-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)[J]. J Interferon Cytokine Res, 2008, 28(3):133-139. DOI:10.1089/jir.2007.0992.
[18] Zhao L, Ching LM, Kestell P, et al. The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice[J]. Br J Cancer, 2002, 87(4):465-470. DOI:10.1038/sj.bjc.6600479.
[19] 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[J]. Cell Rep, 2015, 11(7):1018-1030. DOI:10.1016/j.celrep.2015.04.031.
[20] Kim S, Li L, Maliga Z, et al. Anticancer flavonoids are mouse-selective STING agonists[J]. ACS Chem Biol, 2013, 8(7):1396-1401. DOI:10.1021/cb400264n.
[21] Wang H, Hu S, Chen X, et al. cGAS is essential for the antitumor effect of immune checkpoint blockade[J]. Proc Natl Acad Sci USA, 2017, 114(7):1637-1642. DOI:10.1073/pnas.1621363114.
[22] Tang CH, Zundell JA, Ranatunga S, et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells[J]. Cancer Res, 2016, 76(8):2137-2152. DOI:10.1158/0008-5472. CAN-15-1885.
[23] Li T, Cheng H, Yuan H, et al. Antitumor activity of cGAMP via stimulation of cGAS-cGAMP-STING-IRF3 mediated innate immune response[J]. Sci Rep, 2016, 6:19049. DOI:10.1038/srep19049.
[24] Temizoz B, Kuroda E, Ohata K, et al. TLR9 and STING agonists synergistically induce innate and adaptive type-Ⅱ IFN[J]. Eur J Immunol, 2015, 45(4):1159-1169. DOI:10.1002/eji.201445132.
[25] Chandra D, Quispe-Tintaya W, Jahangir A, et al. STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer[J]. Cancer Immunol Res, 2014, 2(9):901-910. DOI:10.1158/2326-6066. CIR-13-0123.
[26] Wang Z, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice[J]. Cancer Immunol Immunother, 2015, 64(8):1057-1066. DOI:10.1007/s00262-015-1713-5.
[27] Fu J, Kanne DB, Leong M, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade[J]. Sci Transl Med, 2015, 7(283):283ra52. DOI:10.1126/scitranslmed.aaa4306.
[28] Nakamura T, Miyabe H, Hyodo M, et al. Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma[J]. J Control Release, 2015, 216:149-157. DOI:10.1016/j.jconrel.2015.08.026.
[29] Ahn J, Xia T, Konno H, et al. Inflammation-driven carcinogenesis is mediated through STING[J]. Nat Commun, 2014, 5:5166. DOI:10.1038/ncomms6166.
[30] Härtlova A, Erttmann SF, Raffi FA, et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity[J]. Immunity, 2015, 42(2):332-343. DOI:10.1016/j.immuni.2015.01.012.
[31] Luthra P, Aguirre S, Yen BC, et al. Topoisomerase Ⅱ inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion[J]. mBio, 2017, 8(2):e00368-17. DOI:10.1128/mBio.00368-17.
[32] Erdal E, Haider S, Rehwinkel J, et al. A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1[J]. Genes Dev, 2017, 31(4):353-369. DOI:10.1101/gad.289769.116.
[33] Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors[J]. Immunity, 2014, 41(5):843-852. DOI:10.1016/j.immuni.2014.10.019.
[34] Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity[J]. Nat Commun, 2017, 8:15618. DOI:10.1038/ncomms15618.
[35] Liang H, Deng L, Hou Y, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance[J]. Nat Commun, 2017, 8(1):1736. DOI:10.1038/s41467-017-01566-5.
[36] Hou Y, Liang H, Rao E, et al. Non-canonical NF-κB antagonizes STING sensor-mediated DNA sensing in radiotherapy[J]. Immunity, 2018, 49(3):490-503.e4. DOI:10.1016/j.immuni.2018.07.008.