METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity

Although immunotherapy improves clinical outcomes in several types of malignancies, as an immunologically cold tumor, pancreatic ductal adenocarcinoma is arrantly resistant to immunotherapy. However, the role of N6 methyladenosine modification in the immune microenvironment of PDAC is still poorly understood. Here, we demonstrate that METTL3, the key regulator of m6A modification, is downregulated in PDAC, and negatively correlates with PDAC malignant features. Elevated METTL3 suppresses PDAC growth and overcomes resistance to immune checkpoint blockade. Mechanistically, METTL3 promotes the accumulation of endogenous double-stranded RNA through protecting m6A transcripts from further Adenosine-to-inosine editing. The dsRNA stress activates RIG-1-like receptors to enhance anti-tumor immunity, finally suppressing PDAC progression.