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A major barrier is therapeutic radiation-induced radioresistance in rectal cancer cells alongside toxicity in normal tissues. This review explains mechanistic drivers of radioresistance during and after radiotherapy, focusing on tumor microenvironment changes, radiation-induced hypoxia, and stromal functional alterations involving TAMs and CAFs. It also summarizes pathway regulation (PI3K/AKT, Wnt/β-catenin, hippo) and emerging radiosensitization strategies.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/understanding-the-molecular-mechanism-responsible-for-developing-therapeutic-radiation-induced-radioresistance-of-rectal-cancer-and-improving-the-clinical-outcomes-of-radiotherapy-a-review/331922/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/understanding-the-molecular-mechanism-responsible-for-developing-therapeutic-radiation-induced-radioresistance-of-rectal-cancer-and-improving-the-clinical-outcomes-of-radiotherapy-a-review/331922.png","ImageObject",300,407,{"name":92,"@type":93},"Finn","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",15,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why does radiotherapy play a central role in rectal cancer management?","Question",{"text":113,"@type":114},"External beam radiotherapy is the most common approach because it limits cancer progression and significantly reduces the risk of local recurrence.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What are the key drawbacks of therapeutic radiation in rectal cancer?",{"text":118,"@type":114},"Therapeutic radiation-induced radioresistance in rectal cancer cells and toxicity to normal tissues are major drawbacks.",{"name":120,"@type":111,"acceptedAnswer":121},"Which tumor microenvironment and signaling elements are highlighted as drivers of radioresistance?",{"text":122,"@type":114},"The review emphasizes radiation-mediated tumor microenvironment changes, hypoxia, stromal alterations involving TAMs and CAFs, and signaling pathways including PI3K/AKT, Wnt/β-catenin, and the hippo pathway.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},331922,1789995787,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":105,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},34359740700684,"https://ap-avatar.wpscdn.com/avatar/1f400023980c374ae676?_k=1777273430885731487","CANCER BIOLOGY & THERAPY  \n2024, VOL. 25, NO. 1, 2317999 [https://doi.org/10.1080/15384047.2024.2317999](https://doi.org/10.1080/15384047.2024.2317999)  \nREVIEW  \nUnderstanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy-A review  \nSamatha M Jaina, Shruthi Nagainallur Ravichandrana, Makalakshmi Murali Kumara, Antara Banerjeea, Alexander SunZhangb, Hong Zhangc, Rupak Pathakd, Xiao-Feng Sune, and Surajit Pathak a  \naFaculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India; bDepartment of Oncology-Pathology, BioClinicum, Karolinska Institutet, Stockholm, Sweden; cSchool of Medicine, Department of Medical Sciences, Orebro University, Örebro, Sweden; dDivision of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA; e Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden  \nABSTRACT  \nRectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as – the PI3K/AKT pathway, Wnt/β-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.  \nSchematic diagram representing the role of radiosensitizers in enhancing radiosensitivity.  \nARTICLE HISTORY  \nReceived 16 August 2023 Revised 18 December 2023 Accepted 8 February 2024  \nKEYWORDS  \nRectal cancer; radiotherapy; DNA double-strand breaks; radiosensitizers  \nCONTACT Xiao-Feng Sun  [xiao-feng.sun@liu.se](xiao-feng.sun@liu.se) Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, 58183, Sweden; Rupak Pathak  [RPathak@uams.edu](RPathak@uams.edu)  Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Surajit Pathak  [drsurajitpathak@care.edu.in](drsurajitpathak@care.edu.in)  Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, 603103, India  \n© 2024 The Author(s) . Published with license by Taylor & Francis Group, LLC.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License ([http://creativecommons.org/licenses/by","cbCaij2AtwmuW6y9","https://ap.wps.com/l/cbCaij2AtwmuW6y9","pdf",3762580,"English","# Abstract\n# Radiotherapy in rectal cancer\n## Background and epidemiology\n## Treatment context and survival\n## Radiotherapy techniques and toxicity considerations\n# Molecular mechanisms of radioresistance (review overview)","[{\"question\":\"Why does radiotherapy play a central role in rectal cancer management?\",\"answer\":\"External beam radiotherapy is the most common approach because it limits cancer progression and significantly reduces the risk of local recurrence.\"},{\"question\":\"What are the key drawbacks of therapeutic radiation in rectal cancer?\",\"answer\":\"Therapeutic radiation-induced radioresistance in rectal cancer cells and toxicity to normal tissues are major drawbacks.\"},{\"question\":\"Which tumor microenvironment and signaling elements are highlighted as drivers of radioresistance?\",\"answer\":\"The review emphasizes radiation-mediated tumor microenvironment changes, hypoxia, stromal alterations involving TAMs and CAFs, and signaling pathways including PI3K/AKT, Wnt/β-catenin, and the hippo pathway.\"}]","Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review | PDF",1789995760,38]