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

文献类型： 外文期刊

作者： Cao, Limin;Wang, Li;Li, Zhihong;Wei, Xia;Ding, Jinqiu;Zhou, Chun;Chen, Xia;Huang, Zhicheng;Shao, Zhugui;Shen, Junchen;Lou, Hongfei;Zhao, Keqing;Huang, Yuwei;Yang, Yuanqin;Liu, Han;Sun, Yumeng;Niu, Junling;Jiang, Shan;Lu, Rong;Tang, Longhai;Zhang, Xiaoming;Zhang, Haibing;Xiao, Yichuan;Chen, Jianfeng;Ma, Shixin;Gao, Chengjiang;Meng, Guangxun;Liu, Li;Qiu, Zhaozhu;Wang, Haopeng;Deng, Liufu;Ye, Youqiong;Jia, Xin-Ming;Li, Huabin;Xiao, Hui

作者机构：

期刊名称： SCIENCE IMMUNOLOGY

ISSN： 2470-9468

年卷期： 2025 年 10 卷 108 期

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收录情况： SCIE（2025版）

摘要： 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)P2] 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-alpha/beta, which up-regulate granzymes and IFN-gamma 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.

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