Methionine Restriction Promotes cGAS Activation and Chromatin Untethering through Demethylation to Enhance Antitumor Immunity

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA to activate type I interferon and plays essential roles in antitumor immunity. However, it remains unclear whether cGAS-mediated antitumor activity is affected by nutrient status. Here our study reports that methionine deprivation enhances cGAS activity via blocking its methylation, which is catalyzed by methyltransferase Suv39h1 and erased by demethylase KDM4B. 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 the nutrient stress promotes cGAS activity via reversible methylation, and suggest a potential therapeutic strategy of targeting cGAS methylation in cancer treatment.