Interplay Between Epigenetics and Reactive Oxygen Species in Tumor Radioresistance: Mechanisms and Therapeutic Strategies for Radiotherapy.

Radiotherapy efficacy is constrained by tumor radioresistance, which arises in part from the interplay between reactive oxygen species (ROS) and epigenetic regulation. This review systematically synthesizes the bidirectional "epigenetics-ROS interactive network" that governs tumor radiosensitivity. We propose that this network operates through three core principles: stress adaptation (acute ROS triggers transient epigenetic adjustments for redox recovery), malignant reinforcement (chronic ROS drives stable epigenetic reprogramming toward therapy resistance), and contextual determinacy (cellular outcomes depend on integrated ROS-epigenetic patterns rather than individual signals). Mechanistically, we delineate four regulatory layers including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, through which the epigenetic machinery controls ROS homeostasis, and conversely, how radiation-induced ROS reshape the epigenetic landscape via oxidative modification of epigenetic enzymes and signaling pathways. These bidirectional interactions form feedback circuits that ultimately dictate whether cells undergo repair, senescence, apoptosis, or ferroptosis. Based on this mechanism, we propose a context-dependent decision framework that matches four distinct combination strategies (ROS amplification, epigenetic priming, hypoxia relief, and multi-pathway cell death induction) with four tumor subtypes defined by their oxidative and epigenetic profiles. We also identify five translational roadblocks including toxicity, delivery inefficiency, manufacturing scalability, regulatory uncertainty, and preclinical-clinical discordance. Resolving these barriers is essential for unlocking the therapeutic potential of this regulatory axis. Strategically targeting the epigenetics-ROS network offers a transformative paradigm for overcoming radioresistance and personalizing cancer radiotherapy.