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Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity

Lan Fang,Yun Hao,Haihong Yu,Xuemei Gu,Qiao Peng,Huimin Zhuo,Yaxu Li,Zhiyuan Liu,Jia Wang,Yunfei Chen,Jiawen Zhang,Hongling Tian,Yaohui Gao,Renyuan Gao,Hongqi Teng,Zezhi Shan,Jiali Zhu,Zhiqiang Li,Yu'e Liu,Yiyi Zhang,Fei Yu,Zhang Lin,Yujun Hao,Xin Ge,Jian Yuan,Hong-Gang Hu,Yanlei Ma,Huan-Long Qin,Ping Wang

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.