Mechanistically, we revealed that SETD2‐H3K36me3 loss directly downregulated Cxadr expression in pancreatic tumor cells, allowing for PI3K‐AKT activation and the release of excessive CXCL1 and GM‐CSF, which attracted neutrophils and reprogrammed them toward an immunosuppressive phenotype. Here, CSF2 is linked to pancreatic neoplasm.