肿瘤免疫微环境中cGAS-STING信号通路的细胞间信号传递  

Cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment

作　　者：王梦秋 徐平龙 吴芑柔 WANG Mengqiu;XU Pinglong;WU Qirou(Life Sciences Institute,ZhejiangUniversity,Hangzhou 310058,China;Key Laboratory of Biosystems Homeostasis and Protection,Ministry of Education,Zhejiang Provincial Key Laboratory for CancerMolecular Cell Biology,Zhejiang University,Hangzhou 310058,China;Institute ofIntelligent Medicine,Hangzhou Global Scientific and Technological Innovation Center,Zhejiang University,Hangzhou 311200,China;Cancer Center,Zhejiang University,Hangzhou 310058,China)

机构地区：[1]浙江大学生命科学研究院,浙江杭州310058 [2]浙江大学生命系统稳态与保护教育部重点实验室、浙江省癌症分子细胞生物学重点实验室,浙江杭州310058 [3]浙江大学杭州国际科创中心智能医药研究所,浙江杭州311200 [4]浙江大学癌症研究院,浙江杭州310058

出　　处：《浙江大学学报（医学版）》2024年第1期15-24,共10页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(31725017,31830052);国家重点研发计划(2021YFA1301401)。

摘　　要：环鸟苷酸-腺苷酸合成酶(cGAS)-干扰素基因刺激因子(STING)信号通路是肿瘤免疫治疗中备受关注的靶点。模式识别受体cGAS识别胞质双链DNA(dsDNA),生成第二信使2´3´-环鸟苷酸-腺苷酸(cGAMP),活化接头蛋白STING,介导干扰素和促炎性细胞因子的产生,从而促进肿瘤免疫。肿瘤免疫微环境中cGAS-STING通路的细胞间信号传递维持并增强天然免疫应答,推动适应性免疫的发展。基于膜系统的细胞外囊泡运输、吞噬作用和细胞膜融合传递dsDNA、cGAMP以及活化的STING蛋白,加强免疫监视和炎症应答。基于膜蛋白的缝隙连接、膜转运蛋白传递cGAMP和dsDNA对免疫调节至关重要。此外,配体-受体反应传递干扰素进一步放大抗肿瘤免疫反应。本文描述了肿瘤免疫微环境中cGAS-STING通路的细胞间信号传递及其调控,讨论这些机制如何影响和调节肿瘤免疫过程,以及针对这些信号传递机制的潜在干预和免疫治疗策略。Targeting cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway is a promising strategy for tumor treatment.The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of a second messenger 2´3´-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING.Notably,in tumor immune microenvironment,key components of cGAS-STING pathway are transferred among neighboring cells.The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity.The membranebased system,including extracellular vesicles transport,phagocytosis and membrane fusion transmit dsDNA,cGAMP and activated STING,enhances the immune surveillance and inflammatory responses.The membrane proteins,including a specific protein channel and intercellular gap junctions,transfer cGAMP and dsDNA,which are crucial to regulate immune responses.The ligand-receptor interactions for interferon transmission amplifies the anti-tumor response.This review elaborates on the regulatory mechanisms of cell-tocell communications of cGAS-STING pathway in tumor immune microenvironment,explores how these mechanisms modulate immunological processes and discusses potential interventions and immunotherapeutic strategies targeting these signaling cascades.

关 键 词：肿瘤微环境 环鸟苷酸-腺苷酸合成酶-干扰素基因刺激因子 细胞间信号传递 双链DNA 肿瘤免疫 免疫应答 综述 

分 类 号：R392[医药卫生—免疫学]