Epigenetic therapy combined with radiotherapy reshapes tumor immune response

Radiotherapy is essential for local tumor control, and increasing evidence highlights its ability to trigger systemic immune responses. However, the integration of this systemic activation into clinical treatment regimens remains limited. The immunosuppressive environment in the tumor microenvironment (TME) is a key barrier to translating the systemic immune effects of radiotherapy into clinical practice. Recently, epigenetic regulation has emerged as a key mechanism in modulating gene expression, closely linked to tumor initiation, progression, and immune evasion. Epigenetic inhibitors can influence immune cells and checkpoint molecules by altering DNA methylation and histone modifications, thus reshaping the TME. This review examines how radiotherapy induces epigenetic reprogramming to modulate immune responses and discusses how aberrant epigenetic alterations in tumor cells may impact radiotherapy-driven inflammatory responses. Additionally, this study provides an overview of clinical studies combining epigenetic inhibitors with radiotherapy and immunotherapy and suggests the potential role of epigenetic biomarkers in patient stratification for clinical applications.