Research progress of cGAS-STING signaling pathway modulators in immunotherapy
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摘要:
环鸟嘌呤-腺嘌呤核苷酸合成酶（cGAS）-干扰素基因刺激蛋白（STING）信号通路感知细胞质中的异常双链DNA后，诱导Ⅰ型干扰素（IFN- Ⅰ ）和促炎细胞因子表达，从而激活宿主的免疫应答，增强机体抗肿瘤免疫反应和抗病原体感染。但是，cGAS-STING信号通路的持续激活会驱动自身免疫性疾病、衰老相关炎症和神经退行性病变等疾病。本文阐述了cGAS-STING信号通路参与调控多种免疫相关性疾病发生发展的机制，重点回顾了STING激动剂、cGAS抑制剂以及STING抑制剂的研发进展，为cGAS-STING调节剂的研发提供更多理论参考。
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关键词:
- cGAS-STING信号通路 /
- STING激动剂 /
- cGAS抑制剂 /
- STING抑制剂 /
- 免疫治疗
Abstract:Upon monitoring cytoplasmic aberrant double-stranded DNA, cGAS-STING signaling pathway induces the expression of type I interferons and pro-inflammatory cytokines, which activates the host immune response and enhances anti-tumor immune response and resistance to pathogen infection. However, sustained activation of the cGAS-STING signaling pathway drives diseases such as autoimmune diseases, aging-associated inflammation, and neurodegenerative pathologies. Herein, we describe the mechanism by which cGAS-STING signaling pathway participates in regulating the development of various immune-related diseases, with a particular review of the research and development progress of STING agonists, cGAS inhibitors, and STING inhibitors, aiming to provide some theoretical reference for the future development of cGAS-STING modulators.
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Keywords:
- cGAS-STING signaling pathway /
- STING agonist /
- cGAS inhibitor /
- STING inhibitor /
- immunotherapy
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表 1 cGAS-STING信号通路参与调控多种免疫相关疾病的发生发展
疾病 疾病类型 与cGAS-STING信号通路的相关性 治疗方法 参考
文献肿瘤 抑癌 激活cGAS-STING信号通路，激发级联抗肿瘤免疫反应 cGAS/STING激动剂 [11] 促癌 cGAS-STING信号通路持续激活状态 cGAS/STING抑制剂 [14−15] 病原体感染 病毒 病毒的结构蛋白与STING相互作用，抑制STING通路的激活 cGAS/STING激动剂 [16−17] 细菌 抑制环状二核苷酸（CDNs）与STING蛋白结合 cGAS/STING激动剂 [21] 真菌 STING转位到吞噬体，抑制Src相关的Syk磷酸化，从而抑制抗真菌天然免疫信号通路 cGAS/STING抑制剂 [22] 自身免疫性疾病 STING相关血管病变 STING基因功能获得性突变 STING抑制剂 [23] Aicardi-Goutières综合征 核酸代谢紊乱有关的疾病 cGAS/STING抑制剂 [25] 胶原诱导性关节炎 dsDNA异常积累促进STING异常激活 cGAS/STING抑制剂 [27] COPA综合征 STING在高尔基体积累并自激活 STING抑制剂 [28] 系统性红斑狼疮 血清中cGAMP水平升高，促进cGAS-STING信号通路异常激活 cGAS/STING抑制剂 [29] 类风湿关节炎 cGAS-STING信号通路异常激活 cGAS/STING抑制剂 [30] 衰老 衰老 在cGAS缺陷或STING缺陷细胞/小鼠中观察到抗衰老保护作用 cGAS/STING抑制剂 [33] 神经退行性病变 阿尔茨海默病 I型干扰素加重神经炎症并促进阿尔茨海默病发展 cGAS/STING抑制剂 [34] 亨廷顿病 活性氧促进线粒体损伤，激活cGAS-STING信号通路 cGAS/STING抑制剂 [35] 帕金森病 cGAS-STING信号通路长期激活导致帕金森病的恶化 cGAS/STING抑制剂 [36] 共济失调-毛细血管扩张症 dsDNA激活cGAS-STING信号通路 cGAS/STING抑制剂 [37] 
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表 2 STING激动剂研发进展
分类 化合物名称 适应证 给药方式 试验阶段 临床编号/参考文献 CDNs类 ADU-S100 复发性或转移性头颈部鳞状细胞癌 瘤内注射 临床Ⅱ期（终止） NCT03937141 MK-1454 头颈部鳞状细胞癌 瘤内注射 临床Ⅱ期 NCT04220866 E7766 晚期实体瘤；淋巴瘤 瘤内注射 临床Ⅰ期 NCT04144140 TAK-676 成人晚期或转移性实体瘤 静脉注射 临床Ⅰ期 NCT04420884 SB11285 晚期或转移性实体瘤 静脉注射 临床Ⅰ期 NCT04096638 BI1387446 晚期实体瘤 瘤内注射 临床Ⅰ期 NCT04147234 IMSA101 晚期实体瘤 瘤内注射 临床Ⅰ/Ⅱ期 NCT04020185 BMS-986301 晚期实体瘤 静脉、瘤内、肌肉注射 临床Ⅰ期 NCT03956680 DN-015089 实体瘤 皮下、瘤内注射 临床Ⅰ期 CTR20212462 非CDNs类 diABZI 结肠癌 腹腔注射 临床前 [10] SR-717 黑色素瘤 腹腔注射 临床前 [41] MSA-2 结肠癌 瘤内、皮下注射；口服 临床前 [42] SNX281 晚期实体瘤 静脉注射 临床Ⅰ期 NCT04609579 HG381 晚期实体瘤 静脉注射 临床Ⅰ期 NCT04998422 ONO-7914 晚期或转移性实体癌 - 临床Ⅰ期 jRCT2031210530 KL340399 晚期实体瘤 瘤内注射 临床Ⅰ期 NCT05549804
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表 3 cGAS抑制剂研发进展
化合物名称 功 能 种属特异性 体内或体外模型 体内或体外活性 参考文献 PF-06928215 抑制cGAS酶活 人源cGAS - - [43] CU-76 抑制cGAS酶活 人源cGAS THP-1细胞 抑制人源cGAS蛋白活性 [44] RU.521 抑制cGAS酶活 鼠源cGAS AGS小鼠模型 抑制I型干扰素的表达 [45] G150 抑制cGAS酶活 人源cGAS THP1细胞
RAW 264.7细胞抑制dsDNA诱导的cGAS活性 [46] PAH 抑制cGAS酶活 人/鼠源cGAS AGS小鼠模型 改善自身DNA诱导的自身炎症反应 [47] 奎纳克林、羟氯喹 抑制dsDNA/cGAS结合 人/鼠源cGAS Trex1−/−小鼠模型 对AGS/SLE小鼠的治疗有效 [48] Suramin 抑制dsDNA/cGAS结合 人源cGAS THP1细胞 抑制cGAS介导的I型干扰素反应 [49] VENT-03 抑制cGAS 人源cGAS Trex1−/−小鼠模型 抑制炎症，提高生存率 [8]
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表 4 STING抑制剂研发进展
化合物名称 功 能 种属特异性 体内或体外模型 体内或体外活性 参考文献 C-178, C-176 抑制STING棕榈酰化 鼠源 Trex1−/−小鼠模型 改善全身炎症 [51] C-170, C-171 抑制STING棕榈酰化 人/鼠源 Trex1−/−小鼠模型 改善全身炎症 [51] H-151 抑制STING棕榈酰化 人/鼠源 Trex1−/−小鼠模型 改善全身炎症 [51] NO2-FAs 抑制STING棕榈酰化 人/鼠源 SAVI患者成纤维细胞 抑制IFN- Ⅰ的产生 [52] 4-OI 阻断STING的棕榈酰化和寡聚化 鼠源 BMDMs细胞
Raw264.7细胞
MEFs细胞抑制cGAS-STING信号通路 [53] BB-Cl-脒 共价修饰Cys148抑制STING寡聚 人/鼠源 BMDMs细胞
外周血单核细胞
AGS的Trex1D18N/D18N小鼠模型抑制小鼠和人类细胞中STING的激活，提高小鼠存活率 [54] LB244 共价修饰C292来抑制STING寡聚 人/鼠源 人单核细胞
BMDMs细胞阻断STING的共价修饰,抑制cGAS-STING信号通路 [55] Astin C 特异性结合STING的C端配体结合域 人/鼠源 Trex1−/−BMDMs细胞和Trex1−/−小鼠模型 抑制IFN- Ⅰ和促炎细胞因子的表达并减轻自身炎症反应 [56] Compound 18 占据STING二聚体的结合口袋 人/鼠源 THP1细胞 抑制cGAMP诱导的IFN-β的产生 [57] SN-011 与CDNs竞争STING内源性配体结合口袋 人/鼠源 Trex1−/−小鼠模型 改善自身免疫疾病 [58]
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