Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review

Sep 21, 2026

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Rectal cancer causes substantial cancer-related mortality, and while treatment often combines surgery, chemotherapy, and immunotherapy, external beam radiotherapy is central for limiting progression and reducing local recurrence. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Radiotherapy in rectal cancer

Background and epidemiology

Treatment context and survival

Radiotherapy techniques and toxicity considerations

Molecular mechanisms of radioresistance (review overview)

CANCER BIOLOGY & THERAPY 2024, VOL. 25, NO. 1, 2317999 [https://doi.org/10.1080/15384047.2024.2317999](https://doi.org/10.1080/15384047.2024.2317999) REVIEW Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy-A review Samatha M Jaina, Shruthi Nagainallur Ravichandrana, Makalakshmi Murali Kumara, Antara Banerjeea, Alexander SunZhangb, Hong Zhangc, Rupak Pathakd, Xiao-Feng Sune, and Surajit Pathak a aFaculty 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 ABSTRACT Rectal 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. Schematic diagram representing the role of radiosensitizers in enhancing radiosensitivity. ARTICLE HISTORY Received 16 August 2023 Revised 18 December 2023 Accepted 8 February 2024 KEYWORDS Rectal cancer; radiotherapy; DNA double-strand breaks; radiosensitizers CONTACT 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 © 2024 The Author(s) . Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([http://creativecommons.org/licenses/by

FAQs

Why does radiotherapy play a central role in rectal cancer management?

External beam radiotherapy is the most common approach because it limits cancer progression and significantly reduces the risk of local recurrence.

What are the key drawbacks of therapeutic radiation in rectal cancer?

Therapeutic radiation-induced radioresistance in rectal cancer cells and toxicity to normal tissues are major drawbacks.

Which tumor microenvironment and signaling elements are highlighted as drivers of radioresistance?

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.

Sep 21, 2026

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