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This review systematically synthesizes the bidirectional \u201cepigenetics\u2010ROS interactive network\u201d 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\u2010epigenetic patterns rather than individual signals). Mechanistically, we delineate four regulatory layers including DNA methylation, histone modifications, non\u2010coding RNAs, and chromatin remodeling, through which the epigenetic machinery controls ROS homeostasis, and conversely, how radiation\u2010induced 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\u2010dependent decision framework that matches four distinct combination strategies (ROS amplification, epigenetic priming, hypoxia relief, and multi\u2010pathway 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\u2010clinical discordance. Resolving these barriers is essential for unlocking the therapeutic potential of this regulatory axis. Strategically targeting the epigenetics\u2013ROS network offers a transformative paradigm for overcoming radioresistance and personalizing cancer radiotherapy.<\/jats:p>","DOI":"10.1002\/cam4.72388","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:42:21Z","timestamp":1792143741000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interplay Between Epigenetics and Reactive Oxygen Species in Tumor Radioresistance: Mechanisms and Therapeutic Strategies for Radiotherapy"],"prefix":"10.1002","volume":"15","author":[{"given":"Zhengmao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical and Radiation Oncology The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical and Radiation Oncology The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical and Radiation Oncology The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Medical and Radiation Oncology The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical and Radiation Oncology The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9946-9869","authenticated-orcid":false,"given":"Wenjian","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medical and Radiation Oncology The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1247268"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.3934\/biophy.2024019"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.002"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2024.111502"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13030312"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.59"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2023.130386"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010024\u201000757\u20109"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111359"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001341\u20107"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2008.09.016"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/38664"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2025.09.019"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rechem.2023.101253"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232112815"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1515\/medgen\u20102024\u20102014"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.1071786"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2019.01.024"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122659"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40164\u2010023\u201000451\u2010w"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb46110755"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7267"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr300063r"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/09553008714552571"},{"key":"e_1_2_14_26_1","volume-title":"Rate Constants and G\u2010Values for the Simulation of the Radiolysis of Light Water Over the Range 0\u2013300\u00b0C","author":"Elliot A. 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