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Although patient survival rates have improved through various therapeutic approaches, including surgery, chemotherapy, and radiotherapy, treatment efficacy remains limited once tumor metastasis occurs. Among various cancer treatment strategies, radiotherapy plays a crucial role. Along with surgery and chemotherapy, radiotherapy is a cost\u2010effective single\u2010modality treatment, accounting for approximately 5% of total cancer care costs. The use of radiosensitizing agents such as histone deacetylase inhibitors, 2\u2010deoxy\u2010<jats:sc>d<\/jats:sc>\u2010glucose, enterolactone, and squalene epoxidase can enhance radiotherapy effectiveness. Recent radiosensitization methods involve physical stimuli and chemical radiosensitizers. However, improving their efficacy, durability, and overcoming radioresistance remain significant challenges. This review first introduces current applications of radiotherapy in cancer treatment, the molecular mechanisms underlying its anticancer effects, and its side effects. Second, it discusses the main types of radiosensitizers, their latest applications, and recent challenges in cancer treatment. Finally, it emphasizes on clinical trials of radiosensitizing agents and explores potential biomarkers for radiotherapy response in cancer. Multifunctional nanoparticles have shown greater clinical applicability than single\u2010functional nanoparticles. Future research will focus on enhancing the drug\u2010carrying capacity of nanomaterials to further improve radiotherapy outcomes.<\/jats:p>","DOI":"10.1002\/mco2.70202","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T03:31:59Z","timestamp":1747279919000},"source":"Crossref","is-referenced-by-count":11,"title":["Targeting the Enhanced Sensitivity of Radiotherapy in Cancer: Mechanisms, Applications, and Challenges"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0217-3290","authenticated-orcid":false,"given":"Yuanyuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Oncology Department of\u00a0Radiology Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Organ Transplantation Clinical Medical Research Center of Hubei Province Wuhan  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangqin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Oncology Department of\u00a0Radiology Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Stomatology Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Oncology Department of\u00a0Radiology Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Sichuan Clinical Research Center for Laboratory Medicine West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Oncology Department of\u00a0Radiology Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70025"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31891-8"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13104-019-4653-x"},{"key":"e_1_2_11_7_1","first-page":"0429","article-title":"Nano\u2010Assisted Radiotherapy Strategies: New Opportunities for Treatment of Non\u2010Small Cell Lung Cancer","volume":"7","author":"Zhao L.","year":"2024","journal-title":"Research (Wash D C)"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2014.10.005"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/02841860310010826"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2021.103566"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13014-021-01866-7"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.90"},{"issue":"19","key":"e_1_2_11_13_1","first-page":"1878","article-title":"Regional Nodal Irradiation in Early\u2010Stage Breast Cancer","volume":"373","author":"Whelan T. 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