Radiotherapy enhances anticancer CD8 T cell responses by cGAMP transfer through LRRC8A/C volume-regulated anion channels
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<sub>2</sub>] 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.
Authors
- Wei Xia
- Haibing Zhang (ORCID: https://orcid.org/0000-0002-8814-7378)
- Yumeng Sun (ORCID: https://orcid.org/0000-0002-4701-1810)
- Shixin Ma
- Guangxun Meng (ORCID: https://orcid.org/0000-0003-4634-4661)
- Youqiong Ye (ORCID: https://orcid.org/0000-0001-8332-4710)
- Jinqiu Ding (ORCID: https://orcid.org/0000-0002-8516-421X)
- Hui Xiao (ORCID: https://orcid.org/0000-0001-5304-243X)
- Yuanqin Yang (ORCID: https://orcid.org/0000-0002-0739-3041)
- Xin‐Ming Jia (ORCID: https://orcid.org/0000-0002-7245-5560)
- Chengjiang Gao (ORCID: https://orcid.org/0000-0002-9365-4497)
- Shan Jiang (ORCID: https://orcid.org/0000-0003-4238-8237)
- Zhugui Shao
- Ke‐Qing Zhao (ORCID: https://orcid.org/0000-0001-5703-3768)
- Yichuan Xiao (ORCID: https://orcid.org/0000-0001-7804-6971)
- Zhaozhu Qiu (ORCID: https://orcid.org/0000-0002-9122-6077)
- Jianfeng Chen (ORCID: https://orcid.org/0000-0002-2892-1691)
- Han Liu (ORCID: https://orcid.org/0000-0003-0811-1808)
- Liu L (ORCID: https://orcid.org/0000-0001-9234-457X)
- Wang Li (ORCID: https://orcid.org/0000-0002-5057-3224)
- Xia Chen (ORCID: https://orcid.org/0000-0002-5493-6483)
- Xiaoming Zhang (ORCID: https://orcid.org/0000-0001-6732-9132)
- Haopeng Wang (ORCID: https://orcid.org/0000-0002-4995-0838)
- Junling Niu (ORCID: https://orcid.org/0000-0003-1355-630X)
- Huabin Li (ORCID: https://orcid.org/0000-0002-2477-2879)
- Zhihong Li (ORCID: https://orcid.org/0000-0003-4412-6038)
- Liufu Deng
- Limin Cao (ORCID: https://orcid.org/0009-0008-3121-2299)
- Chun Zhou (ORCID: https://orcid.org/0000-0002-9091-3342)
- Rong Lu (ORCID: https://orcid.org/0000-0002-1905-9366)
- Yuwei Huang (ORCID: https://orcid.org/0009-0006-9478-1785)
- Longhai Tang
- Jingqin Shen (ORCID: https://orcid.org/0000-0003-1487-5994)
- Hongfei Lou
- Zhicheng Huang (ORCID: https://orcid.org/0009-0008-1469-2921)
Institutions
- Tongji University (CN)
- Johns Hopkins University (US)
- Shandong University (CN)
- Shanghai Jiao Tong University (CN)
- Johns Hopkins Medicine (US)
- ShanghaiTech University (CN)
- Lanzhou Veterinary Research Institute (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Jiangsu Province Blood Center (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Shanghai Pulmonary Hospital (CN)
- Ministry of Health (OM)
- Chinese Academy of Agricultural Sciences (CN)
- Shenzhen Academy of Aerospace Technology (CN)
- Shanghai Institute of Pharmaceutical Industry (CN)
- University of Chinese Academy of Sciences (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1126/sciimmunol.adn1630
- Citations
- 7
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 5.58