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

  • Sci Immunol. 2025 Jun 27;10(108):eadn1630. doi: 10.1126/sciimmunol.adn1630.
Limin Cao  1 ,  Li Wang  1  2 ,  Zhihong Li  3 ,  Xia Wei  4 ,  Jinqiu Ding  1 ,  Chun Zhou  5  6 ,  Xia Chen  7 ,  Zhicheng Huang  1 ,  Zhugui Shao  1  8 ,  Junchen Shen  1 ,  Hongfei Lou  5 ,  Keqing Zhao  5 ,  Yuwei Huang  9 ,  Yuanqin Yang  4 ,  Han Liu  6 ,  Yumeng Sun  1 ,  Junling Niu  1 ,  Shan Jiang  1 ,  Rong Lu  10 ,  Longhai Tang  10 ,  Xiaoming Zhang  1 ,  Haibing Zhang  6 ,  Yichuan Xiao  6 ,  Jianfeng Chen  11 ,  Shixin Ma  12 ,  Chengjiang Gao  8 ,  Guangxun Meng  1 ,  Li Liu  3 ,  Zhaozhu Qiu  13 ,  Haopeng Wang  9 ,  Liufu Deng  14 ,  Youqiong Ye  4 ,  Xin-Ming Jia  2 ,  Huabin Li  5 ,  Hui Xiao  1
Affiliations
  • 1. State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2. Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200092, China.
  • 3. State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 200437, China.
  • 4. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5. Center for Allergic and Inflammatory Diseases and Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China.
  • 6. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 7. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China.
  • 8. Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, Shandong, China.
  • 9. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 10. Suzhou Blood Center, Suzhou 215000, Jiangsu, China.
  • 11. State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
  • 12. Shenzhen Medical Academy of Research and Translation, Shenzhen 518107, Guangdong, China.
  • 13. Departments of Physiology, Neuroscience, and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 14. School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 40577443 DOI: 10.1126/sciimmunol.adn1630
Abstract

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-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.

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