BACKGROUND: Immunotherapy, especially with the use of immune checkpoint inhibitors, has demonstrated efficacy for a variety of malignant tumors. However, the potential of immunotherapy for endometrial cancer (EC) with POLE mutations remains underexplored. METHODS: We utilized multiple databases and clinical specimens to investigate the immunogenicity profiles of EC patients carrying POLE mutations. One particular hotspot mutation POLE RESULTS: Tumor- and immune-related pathways were shown to be activated in the POLE CONCLUSIONS: Our study uncovers the pronounced immunogenicity of POLE-mutant EC and characterizes neoantigens that are unique to the POLE