2. Academic Validation
  3. Radiotherapy enhances anticancer CD8 T cell responses by cGAMP transfer through LRRC8A/C volume-regulated anion channels

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

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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