This orchestrated combination of rationally designed gene editing (targeting poliovirus receptor), nano-encapsulated doxorubicin (DOX) chemotherapy, and checkpoint blockade immunotherapy demonstrated enhanced synergistic antitumor activity in pancreatic ductal adenocarcinoma (PDAC) models, achieving tumor regression through enhanced chemotherapy, immunogenic cell death induction, and natural killer (NK) cells activation. This evidence concerns the gene PVR and pancreatic ductal adenocarcinoma.