Mechanistically, we found that KMT2D loss in PDAC cells induces the expression and secretion of activin A, a member of the TGF-β superfamily, and subsequently activates a non-canonical p38 pathway. These Results suggest that KMT2D is a critical tumor suppressor, partly by promoting an immunogenic and tumor-suppressive TME, and the activin A-p38 pathway may serve as a potential therapeutic target for PDAC.