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Life sciences · Review
Experimental Biology and Medicine · October 28, 2026
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Urothelial carcinoma (UC) is a dynamic malignancy characterized by a complex epigenetic landscape. Epigenetic modifications are pivotal in modulating the innate immune response, particularly within the tumor microenvironment (TME), where they profoundly influence natural killer (NK) cell function. Aberrant epigenetic regulation often promotes immune evasion by silencing activating ligands on tumor cells, thereby impairing NK cell-mediated cytotoxicity. Emerging epigenetic therapies, such as histone deacetylase inhibitors (HDACis) and DNA methyltransferase inhibitors (DNMTis), offer significant potential to reprogram the immune landscape and restore anti-tumor immunity. Despite this promise, clinical implementation faces challenges, including the immunosuppressive nature of the TME, NK cell exhaustion, and complex manufacturing limitations. Combining epigenetic agents with NK cell-based immunotherapies represents a robust strategy to overcome these barriers and improve therapeutic outcomes. This review elucidates the epigenetic regulatory mechanisms in UC and emphasizes the necessity of personalized, biomarker-driven treatment strategies to optimize cancer immunotherapy outcomes.