Wen Ziyuan, Sun Fulin, Wang Ruixuan, Wang Wenbo, Zhang Huhu, Yang Fanghao, Wang Mengjun, Wang Yiming, Li Bing
Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.
Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Health Science Center, Qingdao University, Qingdao 266071, China.
Cell Signal. 2025 Oct;134:111914. doi: 10.1016/j.cellsig.2025.111914. Epub 2025 May 30.
As fundamental components of the innate immune system, both cGAS and STING serve as the primary cytosolic DNA sensors and its downstream adaptor protein, respectively. The cGAS-STING signaling axis is activated through DNA recognition and has emerged as a pivotal regulator mediating three key processes: autophagy, apoptosis, and critical biological functions ranging from pro-inflammatory responses to antiviral/antitumor defenses. Recent breakthroughs in tumor immunology have established immunotherapy as the fourth pillar of cancer treatment, alongside traditional approaches such as surgery, chemotherapy, and radiation. Advances in understanding the molecular mechanisms of cGAS-STING signaling have uncovered its dual regulatory potential in tumorigenesis - capable of orchestrating both tumoricidal immune activation and paradoxical tumor progression through microenvironment modulation. The deepening knowledge of its immunological interplay provides a robust theoretical foundation for developing combinatorial strategies. These strategies integrate pathway modulation with immunotherapeutic interventions. Building upon existing research paradigms in cancer immunotherapy, this review specifically focuses on recent progress in exploiting cGAS-STING agonists as next-generation immunotherapeutic agents.
作为先天免疫系统的基本组成部分,cGAS和STING分别作为主要的胞质DNA传感器及其下游衔接蛋白。cGAS-STING信号轴通过DNA识别被激活,并已成为介导三个关键过程的关键调节因子:自噬、凋亡以及从促炎反应到抗病毒/抗肿瘤防御等一系列重要生物学功能。肿瘤免疫学的最新突破已将免疫疗法确立为癌症治疗的第四大支柱,与手术、化疗和放疗等传统方法并驾齐驱。对cGAS-STING信号分子机制的深入理解揭示了其在肿瘤发生中的双重调节潜力——既能通过微环境调节协调杀肿瘤免疫激活,又能导致矛盾的肿瘤进展。对其免疫相互作用的深入了解为开发联合策略提供了坚实的理论基础。这些策略将通路调节与免疫治疗干预相结合。基于癌症免疫治疗现有的研究范式,本综述特别关注利用cGAS-STING激动剂作为下一代免疫治疗药物的最新进展。