Radiotherapy enhances anticancer CD8 T cell responses by cGAMP transfer through LRRC8A/C volume-regulated anion channels

作者：Limin Cao, Wang Li, Zhihong Li, Xia Wei, Jinqiu Ding, Chun Zhou, Xia Chen, Zhicheng Huang, Zhugui Shao, Jingqin Shen, Hongfei Lou, Ke‐Qing Zhao, Yuwei Huang, Yuanqin Yang, Han Liu, Yumeng Sun, Junling Niu, Shan Jiang, Rong Lu, Longhai Tang, Xiaoming Zhang, Haibing Zhang, Yichuan Xiao, Jianfeng Chen, Shixin Ma, Chengjiang Gao, Guangxun Meng, Liu L, Zhaozhu Qiu, Haopeng Wang, Liufu Deng, Youqiong Ye, Xin‐Ming Jia, Huabin Li, Hui Xiao · 发表于：Science Immunology · 年份：2025 · DOI：10.1126/sciimmunol.adn1630 · 被引用次数：14 · 研究领域：interferon and immune responses、Immune Response and Inflammation、Inflammasome and immune disorders

The volume-regulated anion channels (VRACs) transport osmolytes, neurotransmitters, and cyclic GMP-AMP (cGAMP) across the cell membrane to regulate cell volume and host defense. We report that the leucine-rich repeat–containing 8A/C (LRRC8A/C) VRAC plays a crucial role in immune responses to radiotherapy and chemotherapy for cancer. VRACs transfer cGAMP from irradiated cancer cells to infiltrating CD4 and CD8 T cells, thus enhancing their effector functions. TCR signaling acts as a physiological signal to open the VRAC pore through phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and reactive oxygen species (ROS). This allows the rapid uptake of cGAMP and STING activation in mouse and human T cells and induction of interferon-α/β, which up-regulate granzymes and IFN-γ in CD8 T cells. Inhibition of the extracellular hydroxylases CD39 and ENPP1 maintains extracellular ATP and cGAMP, which promotes VRAC-enhanced CD8 T cell anticancer function. Thus, the transfer of cGAMP to T cells by VRACs may be a strategy that can be targeted in future cancer therapies.