Zhang Xiaoyi, Zhang Han, Zhang Jiajia, Yang Mengdie, Zhu Mengqin, Yin Yuzhen, Fan Xin, Yu Fei
Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai, China.
Immunology. 2023 Mar;168(3):375-388. doi: 10.1111/imm.13592. Epub 2022 Oct 25.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell-intrinsic cGAS-STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T-cell priming. Targeting the cGAS-STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS-STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS-STING pathway and analyse the dichotomous roles of the cGAS-STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS-STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS-STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS-STING in RT are explored.
环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激因子（cGAS-STING）通路是先天免疫系统的重要组成部分，对于识别由电离辐射（IR）损伤引起的异常DNA泄漏至关重要。细胞内源性cGAS-STING启动已被揭示在促进干扰素合成和T细胞启动方面具有巨大潜力。靶向cGAS-STING轴已被提议作为提高放射敏感性或增强免疫监视的一种策略。然而，由于受照射肿瘤微环境的生物学复杂性以及cGAS-STING通路在各种生理和病理过程中的广泛参与，该策略中的许多缺陷限制了治疗效果。在此，我们概述了IR激活cGAS-STING通路的分子机制，并分析了cGAS-STING通路在放疗（RT）后调节癌症免疫中的双重作用。然后，基于cGAS-STING通路与IR诱导的其他信号事件（如坏死性凋亡、自噬和其他细胞效应）之间的相互作用，我们讨论了广泛的cGAS-STING信号网络在RT中的免疫调节作用及其潜在的治疗应用。最后，探索了RT中靶向cGAS-STING的联合治疗策略的最新进展。
