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While neoadjuvant (chemo)radiotherapy regimens remain a cornerstone of treatment, up to 20\u201340% of tumours exhibit or develop resistance to ionising radiation, limiting therapeutic options and leading to disease evolution. This review offers a comprehensive insight into the complex biological and molecular mechanisms underlying RC radioresistance within the fundamental 6Rs of radiobiology: Repair, Reoxygenation, Redistribution, Radiosensitivity, Repopulation, and Reactivation. More specifically, DNA damage repair pathways, cell cycle regulation, hypoxia, transcriptional plasticity regulators such as cancer stem cells, and non-coding RNAs are comprehensively reviewed. Additionally, the critical roles of tumour-infiltrating lymphocytes, cancer-associated macrophages, and inflammatory cancer-associated fibroblasts in radioresistance are also dissected, which collectively shape an immunosuppressive and pro-metastatic niche following radiotherapy. Furthermore, a less explored mechanism, namely the metabolic rewiring of cancer cells after radiotherapy, is proposed as a new 7th R of Radiobiology, namely \u201cReprogramming\u201d, that enables tumour survival and promotes aggressive phenotypes. This new perspective adds a new layer of complexity to the molecular understanding of RC resistance and provides a mechanistic insight currently missing in radiobiology research. Additionally, advanced experimental models, such as spheroids, patient-derived organoids, and animal models, are discussed as valuable platforms for pre-clinical research and therapeutic testing. This review also integrates mechanistic insights with biomarker-guided clinical decision-making to support RC management. By unravelling these multifactorial mechanisms, we highlight opportunities to develop predictive biomarkers and tailored therapeutic strategies to overcome resistance and improve patient outcomes.<\/jats:p>","DOI":"10.1007\/s10555-026-10359-6","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:44:11Z","timestamp":1784688251000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From bench to bedside: advancing our understanding of radioresistance in rectal cancer"],"prefix":"10.1007","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6457-2356","authenticated-orcid":false,"given":"Diogo","family":"Est\u00eav\u00e3o","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5630-8635","authenticated-orcid":false,"given":"Miguel","family":"da Cruz-Ribeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7424-1830","authenticated-orcid":false,"given":"Diogo","family":"Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7078-7257","authenticated-orcid":false,"given":"Joana","family":"Lencart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-7553","authenticated-orcid":false,"given":"Bruno","family":"Sarmento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5453-760X","authenticated-orcid":false,"given":"Olivier","family":"de Wever","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-0272","authenticated-orcid":false,"given":"Maria J.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7051-040X","authenticated-orcid":false,"given":"T\u00e2nia","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"3","key":"10359_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2022","unstructured":"Bray, F., et al. 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