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Immune checkpoint blockade (ICB) has been explored as a therapeutic strategy to recover the antitumor immune activities against endometrial cancer (EC) escaping from immune surveillance. Increasing evidence has indicated that microsatellite instability (MSI) is a promising biomarker to stratify patients for the ICB therapy. However, even in patients with MSI-High (MSI-H) endometrial cancers, PD-L1 inhibitors, avelumab, and durvalumab have shown only 27% of response rates. Therefore, there is an urgent need to discover new biomarkers for a predictive response to ICB therapy. In this study, we demonstrated that the immune cytolytic activity (CYT) index was significantly correlated with the development and response to immunotherapy in EC. The data showed that higher CYT was significantly associated with better clinical outcome, more antitumor infiltrating immune cells, fewer somatic copy number alterations, but a higher TMB (Tumor mutational burden) status. Furthermore, CYT-high EC was notably relevant to the high expression of various immune checkpoint molecules and showed more effective responses to ICB treatment. Taken together, this study provided new insights into the connection between diverse genetic events and the immune microenvironment in EC and indicated that the CYT status might be a promising biomarker to stratify patients with EC for ICB therapy. [ABSTRACT FROM AUTHOR]