Mechanistically, we revealed that Setd2‐H3K36me3 loss led to ectopic gain of H3K27me3 to downregulate Cxadr in pancreatic tumor cells, which boosted the PI3K‐AKT pathway and excessive expression of CXCL1 and GM‐CSF, thereby contributing to neutrophil recruitment and reprogramming toward an immunosuppressive phenotype. The gene discussed is CSF2; the disease is pancreatic neoplasm.