STING信号通路介导抗肿瘤免疫的研究进展

doi:10.3877/cma.j.issn.2095-1221.2022.03.009

干扰素基因刺激蛋白（STING）是一种跨膜衔接蛋白，在细胞内识别胞质DNA并触发天然免疫应答。STING信号通路异常与自身免疫性疾病及肿瘤的发生发展相关。另一方面，研究显示STING信号通路还可通过提高免疫系统活性抑制肿瘤。因此，了解STING信号通路的功能、调节方式及其在肿瘤调控中的作用机制显得尤为重要。这篇综述着重讲述STING信号通路在肿瘤调控中的研究进展。

关键词: 干扰素刺激基因, STING信号通路, 抗肿瘤免疫

Interferon gene stimulating protein (STING) was a transmembrane adaptor protein, which plays an important role in recognizing cytoplasmic DNA and triggering innate immunity. The abnormal STING pathway was related to not only autoimmune diseases but also tumorigenesis. Increasing data showed that the STING pathway could help cells resist the development of cancer by improving the activity of the immune system. It was particularly important to understand the function, regulation mode and regulatory mechanism of the STING pathway in tumor cells. This review focused on the research status of the STING pathway in tumor cells.

Key words: Interferon-stimulated genes, STING signaling pathway, Anti-tumour immunity

图1 STING信号通路示意图注：dsDNA为双链DNA；ER为内质网；Golgi为高尔基体；cGAMP为环鸟苷酸-腺苷酸；IRF3为干扰素调控因子3；TBK1为TANK结合激酶1；IκBk为核因子κB抑制剂；NF-κB为核因子κB

表1 STING激动剂在小鼠肿瘤模型中的应用

小鼠品系	肿瘤模型	STING激动剂相关治疗	结局
C57BL/6	黑色素瘤	DMXAA	抑制肿瘤生长^[51]
C57BL/6背景的cGas^{- ⁄-}和Tmem173^{- ⁄-}小鼠	结肠癌、肺癌、黑色素瘤转移瘤模型	cGAMP联合Mn²⁺	抑制肿瘤生长和转移^[55]
C57BL/6背景的Pdx-Cre （KPC）转基因小鼠	胰腺导管腺癌	DMXAA	抑制肿瘤生长^[56]
C57BL/6	B16肺转移模型、4T1肺转移模型	吸入气溶胶纳米粒子cGAMP	控制肺转移^[57]
BALB/c	乳腺癌	混合细胞膜纳米囊联合cGAMP	抑制肿瘤术后复发和转移^[58]
FVB/N-Tg小鼠	畸胎瘤	DMXAA联合嵌合抗原受体T细胞	肿瘤得到控制^[59]

表1 STING激动剂在小鼠肿瘤模型中的应用

小鼠品系	肿瘤模型	STING激动剂相关治疗	结局
C57BL/6	黑色素瘤	DMXAA	抑制肿瘤生长^[51]
C57BL/6背景的cGas^{- ⁄-}和Tmem173^{- ⁄-}小鼠	结肠癌、肺癌、黑色素瘤转移瘤模型	cGAMP联合Mn²⁺	抑制肿瘤生长和转移^[55]
C57BL/6背景的Pdx-Cre （KPC）转基因小鼠	胰腺导管腺癌	DMXAA	抑制肿瘤生长^[56]
C57BL/6	B16肺转移模型、4T1肺转移模型	吸入气溶胶纳米粒子cGAMP	控制肺转移^[57]
BALB/c	乳腺癌	混合细胞膜纳米囊联合cGAMP	抑制肿瘤术后复发和转移^[58]
FVB/N-Tg小鼠	畸胎瘤	DMXAA联合嵌合抗原受体T细胞	肿瘤得到控制^[59]

1	Jiang M, Chen P, Wang L, et al. cGAS-STING, an important pathway in cancer immunotherapy[J]. J Hematol Oncol, 2020, 13(1):81. doi: 10.1186/s13045-020-00916-z.
2	Wang Y, Luo J, Alu A, et al. cGAS-STING pathway in cancer biotherapy[J]. Mol Cancer, 2020, 19(1):136. doi: 10.1186/s12943-020-01247-w.
3	Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease[J]. Nat Rev Genet, 2019, 20(11):657-674.
4	Civril F, Deimling T, de Oliveira Mann CC, et al. Structural mechanism of cytosolic DNA sensing by cGAS[J]. Nature, 2013, 498(7454):332-337.
5	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.
6	Xiao TS, Fitzgerald KA. The cGAS-STING pathway for DNA sensing[J]. Mol Cell, 2013, 51(2):135-139.
7	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.
8	Zhang C, Shang G, Gui X, et al. Structural basis of STING binding with and phosphorylation by TBK1[J]. Nature, 2019, 567(7748):394-398.
9	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.
10	Kwon J, Bakhoum SF. The cytosolic DNA-Sensing cGAS-STING pathway in cancer[J]. Cancer Discov, 2020, 10(1):26-39.
11	Zhao B, Du F, Xu P, et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1[J]. Nature, 2019, 569(7758):718-722.
12	周萍萍, 王涛, 孙元, 等. cGAS-STING信号通路:免疫监视的重要机制[J]. 微生物学报, 2021, 61(7):1882-1895.
13	Konno H, Konno K, Barber GN. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling[J]. Cell, 2013, 155(3):688-698.
14	Mukai K, Konno H, Akiba T, et al. Activation of STING requires palmitoylation at the Golgi[J]. Nat Commun, 2016, 7:11932. doi: 10.1038/ncomms11932.
15	Aarreberg LD, Esser-Nobis K, Driscoll C, et al. Interleukin-1β induces mtDNA release to activate innate immune signaling via cGAS-STING[J]. Mol Cell, 2019, 74(4):801-815.e6.
16	Li A, Yi M, Qin S, et al. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy[J]. J Hematol Oncol, 2019, 12(1):35. doi: 10.1186/s13045-019-0721-x.
17	von Roemeling CA, Wang Y, Qie Y, et al. Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity[J]. Nat Commun, 2020, 11(1):1508. doi: 10.1038/s41467-020-15129-8.
18	Ahn J, Ruiz P, Barber GN. Intrinsic self-DNA triggers inflammatory disease dependent on STING[J]. J Immunol, 2014, 193(9):4634-4642.
19	Gkirtzimanaki K, Kabrani E, Nikoleri D, et al. IFNα impairs autophagic degradation of mtDNA promoting autoreactivity of SLE monocytes in a STING-dependent fashion[J]. Cell Rep, 2018, 25(4):921-933.e5.
20	张思桐, 杜和康, 陈骐. TREX1介导的免疫调控在疾病中的作用[J] 中国生物化学与分子生物学报, 2021, 37(11):1415-1422.
21	Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing[J]. Nat Immunol, 2016, 17(10):1142-1149.
22	Muskardin TLW, Niewold TB. Type I interferon in rheumatic diseases[J]. Nat Rev Rheumatol, 2018, 14(4):214-228.
23	Xia T, Konno H, Ahn J, et al. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis[J]. Cell Rep, 2016, 14(2):282-297.
24	Xia T, Konno H, Barber GN. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis[J]. Cell Rep, 2016, 76(22):6747-6759.
25	Ahn J, Konno H, Barber GN. Diverse roles of STING-dependent signaling on the development of cancer[J]. Oncogene, 2015, 34(41): 5302-5308.
26	Szymonowicz KA, Chen J. Biological and clinical aspects of HPV-related cancers[J]. Cancer Biol Med, 2020, 17(4):864-878.
27	Shaikh MH, Bortnik V, McMillan NA, etal. cGAS-STING responses are dampened in high-risk HPV type 16 positive head and neck squamous cell carcinoma cells[J]. Microb Pathog, 2019, 132:162-165.
28	Lau L, Gray EE, Brunette RL, et al. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway[J]. Science, 2015, 350(6260):568-571.
29	Ma Z, Jacobs SR, West JA, et al. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses[J]. Proc Natl Acad Sci U S A, 2015, 112(31):E4306-4315.
30	Ni G, Ma Z, Wong JP, et al. PPP6C negatively regulates STING-dependent innate immune responses[J]. mBio, 2020, 11(4):e01728-20.
31	Li M, Shu HB. Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response[J]. Protein Cell, 2020, 11(8):584-599.
32	Yuen CK, Chan CP, Fung SY, et al. Suppression of type I interferon production by human T-cell leukemia virus type 1 oncoprotein tax through inhibition of IRF3 phosphorylation[J]. J Virol, 2016, 90(8):3902-3912.
33	Bakhoum SF, Cantley LC. The multifaceted role of chromosomal instability in cancer and its microenvironment[J]. Cell, 2018, 174(6):1347-1360.
34	Bakhoum SF, Ngo B, Laughney AM, et al. Chromosomal instability drives metastasis through a cytosolic DNA response[J]. Nature, 2018, 553(7689):467-472.
35	Ng KW, Marshall EA, Bell JC, et al. cGAS-STING and cancer: dichotomous roles in tumor immunity and development[J]. Trends Immunol, 2018, 39(1):44-54.
36	Caliò A, Brunelli M, Gobbo S, et al. Stimulator of interferon genes (STING) immunohistochemical expression in the spectrum of perivascular epithelioid cell (PEC) lesions of the kidney[J]. Pathology, 2021, 53(5):579-585.
37	Motedayen Aval L, Pease JE, Sharma R, et al. Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy[J]. J Clin Med, 2020, 9(10):3323. doi: 10.3390/jcm9103323.
38	Zheng J, Mo J, Zhu T, et al. Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy[J]. Mol Cancer, 2020, 19(1):133. doi: 10.1186/s12943-020-01250-1.
39	Kim H, Kim H, Feng Y, et al. PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity[J]. Sci Transl Med, 2020, 12(551):eaaz5683. doi: 10.1126/scitranslmed.aaz5683.
40	Li J, Duran MA, Dhanota N, et al. Metastasis and immune evasion from extracellular cGAMP hydrolysis[J]. Cancer Discov, 2021, 11(5):1212-1227.
41	Zhou Y, Fei M, Zhang G, et al. Blockade of the phagocytic receptor MerTK on tumor-associated macrophages enhances P2X7R-dependent STING activation by tumor-derived cGAMP[J]. Immunity, 2020, 52(2):357-373.e9.
42	Parkes EE, Walker SM, Taggart LE, et al. Activation of STING-dependent innate immune signaling by s-phase-specific DNA damage in breast cancer[J]. J Natl Cancer Inst, 2017, 109(1):djw199. doi: 10.1093/jnci/djw199.
43	Reisländer T, Groelly FJ, Tarsounas M. DNA damage and cancer immunotherapy: a sting in the tale[J]. Mol Cell, 2020, 80(1):21-28.
44	Hu M, Zhou M, Bao X, et al. ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation[J]. J Clin Invest, 2021, 131(3):e139333. doi: 10.1172/JCI139333.
45	Sen T, Rodriguez BL, Chen L, et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer[J]. Cancer Discov, 2019, 9(5):646-661.
46	Cheng AN, Cheng LC, Kuo CL, et al. Mitochondrial lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles[J]. J Immunother Cancer, 2020, 8(2):e001372. doi: 10.1136/jitc-2020-001372.
47	Baird JR, Friedman D, Cottam B, et al. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors[J]. Cancer Res, 2016, 76(1):50-61.
48	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.
49	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.
50	Wang H, Hu S, Chen X, et al. cGAS is essential for the antitumor effect of immune checkpoint blockade[J]. Proc Natl Acad Sci U S A, 2017, 114(7):1637-1642.
51	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.
52	Su T, Zhang Y, Valerie K, et al. STING activation in cancer immunotherapy[J]. Theranostics, 2019, 9(25):7759-7771.
53	Sokolowska O, Nowis D. STING signaling in cancer cells: important or not?[J]. Arch Immunol Ther Exp (Warsz)2018, 66(2):125-132.
54	Flood BA, Higgs EF, Li S, et al. STING pathway agonism as a cancer therapeutic[J]. Immunol Rev, 2019, 290(1):24-38.
55	Lv M, Chen M, Zhang R, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy[J]. Cell Res, 2020, 30(11):966-979.
56	Jing W, McAllister D, Vonderhaar EP, et al. STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models[J]. J Immunother Cancer, 2019, 7(1):115. doi: 10.1186/s40425-019-0573-5.
57	Liu Y, Crowe WN, Wang L, et al. An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases[J]. Nat Commun, 2019, 10(1):5108. doi: 10.1038/s41467-019-13094-5.
58	Rao L, Wu L, Liu Z, et al. Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis[J]. Nat Commun, 2020, 11(1):4909. doi: 10.1038/s41467-020-18626-y.
59	Xu N, Palmer DC, Robeson AC, et al. STING agonist promotes CAR T cell trafficking and persistence in breast cancer[J]. J Exp Med, 2021, 218(2):e20200844. doi: 10.1084/jem.20200844.

No related articles found!

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Research progress of STING signalling pathways mediated anti-tumor immunity

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Research progress of STING signalling pathways mediated anti-tumor immunity