TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer

Hongwei Lv, Qianni Zong, Cian Chen, Guishuai Lv, Wei Xiang, Fuxue Xing, Guoqing Jiang, Bing Yan, Xiaoyan Sun, Yue Ma, Liang Wang, Zixin Wu, Xiuliang Cui, Hongyang Wang () and Wen Yang ()
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Hongwei Lv: Naval Medical University (Second Military Medical University)
Qianni Zong: Naval Medical University (Second Military Medical University)
Cian Chen: Naval Medical University (Second Military Medical University)
Guishuai Lv: Naval Medical University (Second Military Medical University)
Wei Xiang: University of Science and Technology of China
Fuxue Xing: University of Science and Technology of China
Guoqing Jiang: Yangzhou University
Bing Yan: Yangzhou University
Xiaoyan Sun: Hospital of Zhengzhou University
Yue Ma: University of Science and Technology of China
Liang Wang: Naval Medical University (Second Military Medical University)
Zixin Wu: University of Science and Technology of China
Xiuliang Cui: Naval Medical University (Second Military Medical University)
Hongyang Wang: Naval Medical University (Second Military Medical University)
Wen Yang: Naval Medical University (Second Military Medical University)

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway is vital for anti-tumor immunity, but its role in tumor vasculature is unclear. Herein, using preclinical liver cancer models in Cgas/Sting-deficient male mice, we report that the interdependence between tumor cGAS and host STING mediates vascular normalization and anti-tumor immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates tumor cGAS expression and produces cGAMP. Subsequently, cGAMP is transported via LRRC8C channels to activate STING in endothelial cells, enhancing recruitment and transendothelial migration of lymphocytes. In vivo studies in male mice also reveal that administration of vitamin C, a promising anti-cancer agent, stimulates TET2 activity, induces tumor vascular normalization and enhances the efficacy of anti-PD-L1 therapy alone or in combination with IL-2. Our findings elucidate a crosstalk between tumor and vascular endothelial cells in the tumor immune microenvironment, providing strategies to enhance the efficacy of combinational immunotherapy for liver cancer.

Date: 2024
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DOI: 10.1038/s41467-023-43743-9

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