New perspective on epigenetic modification and immunotherapy in endometrial cancer.

Abstract

Endometrial carcinoma (EC) is a heterogeneous gynecological malignancy. Epigenetic dysregulation promotes the initiation, progression, immune evasion, and therapeutic resistance of EC. Aberrant DNA methylation, histone methylation, histone acetylation, and chromatin remodeling affect key EC-associated pathways and help shape distinct molecular subtypes, including POLE-mutated and mismatch repair-deficient tumours. In this review, we summarize the major epigenetic alterations implicated in EC, with emphasis on DNA methylation regulators, histone-modifying enzymes, and emerging epigenetic targets such as DNMTs, HDACs, LSD1, EZH2, PRMTs, and BET proteins. We further highlight the rapidly evolving immunotherapy landscape in EC, including clinically established or practice-changing regimens such as pembrolizumab-, dostarlimab-, durvalumab-, and lenvatinib-based strategies, particularly in advanced or recurrent disease. In parallel, we discuss investigational epigenetic therapies, including DNMT inhibitors, HDAC inhibitors, LSD1 inhibitors, EZH2-targeted agents, PRMT inhibitors, and BRD4-directed approaches, which are being explored to restore tumour suppressor pathways, enhance tumour immunogenicity, and improve sensitivity to immune checkpoint blockade. By integrating EC-specific epigenetic mechanisms with current immunotherapy advances and ongoing combination strategies, this review provides a clinically oriented perspective on biomarker-guided precision treatment for EC.