This study developed a nanotherapy strategy targeting macrophage‐capping protein (MCP) for effectively suppressing pancreatic ductal adenocarcinoma via dual effects: inhibition of MCP reduces the UFMylation of PIR, thereby decreasing the transcription of GPX4, and promoting the cytoplasmic transportation of HMGB1. Here, GPX4 is linked to pancreatic ductal adenocarcinoma.