Targeting Ferroptosis to Overcome Radioresistance and Enhance Immunotherapy in Colorectal Cancer

Sep 22, 2026

Locally advanced rectal cancer is commonly managed with total neoadjuvant therapy (TNT), combining radiotherapy and systemic chemotherapy to improve tumor downstaging and long-term control, yet responses to radiotherapy vary widely. Radiation sensitivity is shaped by reactive oxygen species, DNA double-strand breaks, and radiation-driven oxidative stress that can promote lipid peroxidation and iron-dependent ferroptosis. Interconnected metabolic regulators, including SLC7A11/SLC3A2, glutathione synthesis, GPX4, iron handling, and lipid remodeling, link ferroptotic vulnerability to antitumor immunity. These mechanisms are especially relevant in colorectal cancer where immunotherapy benefit depends on mismatch repair deficiency or MSI-H status and most tumors are MSS and less responsive.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Highlights

What are the main findings?

What are the implications of the main findings?

Abstract

Keywords

1. Introduction

Review Targeting Ferroptosis to Overcome Radioresistance and Enhance Immunotherapy in Colorectal Cancer Sara Soltani Tehrani 1,2, Samuel Isaac Olson 1,2, Karishma Kundu 1,2, Sylvain Ferrandon 1,2 and Matthew F. Kalady 1,2, * Academic Editor: Jibran Sualeh Muhammad Received: 19 April 2026 Revised: 20 May 2026 Accepted: 22 May 2026 Published: 28 May 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 The Ohio State University James Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; [sara.soltanitehrani@osumc.edu](sara.soltanitehrani@osumc.edu) (S.S.T.); [samuel.olson@osumc.edu](samuel.olson@osumc.edu) (S.I.O.); [karishmakundu95@gmail.com](karishmakundu95@gmail.com) (K.K.); [sylvain.ferrandon@osumc.edu](sylvain.ferrandon@osumc.edu) (S.F.) 2 Division of Colon and Rectal Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH 43210, USA * [Correspondence: matthew.kalady@osumc.edu](Correspondence: matthew.kalady@osumc.edu); Tel.: +1-(614)-293-6774; Fax: +1-(614)-293-4030 Highlights What are the main findings? • Ferroptosis links radiation-induced oxidative stress, chemotherapy response, and antitumor immunity in locally advanced rectal cancer. • The immune effects of ferroptosis are context-dependent, with tumor-cell ferroptosis potentially enhancing immunity and non-selective lipid peroxidation suppressing dendritic-cell and CD8+ T-cell function. What are the implications of the main findings? • Ferroptosis-related biomarkers may improve response prediction in MSS/pMMR rectal cancer, especially in patients considered for watch-and-wait management. • Tumor-selective ferroptosis may provide a rational strategy to enhance radiotherapy, total neoadjuvant therapy, and immune checkpoint blockade without compromising antitumor immunity. Abstract Locally advanced rectal cancer is commonly treated using total neoadjuvant therapy (TNT), which integrates radiotherapy with systemic chemotherapy to improve tumor downstaging, local control, and long-term oncologic outcomes. Despite its central role in treatment, responses to radiotherapy remain highly heterogeneous. While some tumors undergo complete regression, others exhibit intrinsic or acquired treatment resistance, resulting in incomplete tumor control while experiencing treatment-related toxicity. Understanding the biological determinants that govern radiation sensitivity in rectal cancer, therefore, represents a major clinical challenge. Ionizing radiation induces tumor cell death primarily through the generation of reactive oxygen species (ROS) and DNA damage, particularly DNA double-strand breaks. In addition to nuclear DNA injury, radiation-induced oxidative stress can initiate lipid peroxidation within cellular membranes. When lipid peroxide accumulation exceeds the capacity of cellular antioxidant systems, this process can trigger ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid oxidation. Ferroptotic susceptibility is regulated by interconnected metabolic pathways, including cystine transport through system Xc − (SLC7A11/SLC3A2), glutathione synthesis, glutathione peroxidase-4 (GPX4) activity, iron metabolism, and membrane lipid remodeling. Recent evidence further indicates that ferroptosis intersects with antitumor immunity. Ferroptotic tumor cells release oxidized lipid mediators and damage-associated molecular signals that can influence immune activation, while interferon-γ produced by activated CD8+ T cells during immune checkpoint blockade suppresses SLC7A11 expression, limiting cystine uptake and promoting ferroptotic tumor cell death. These findings suggest that ferroptosis represents a mechanistic interface between tumor metabolic vulnerability and immune

FAQs

How does radiation-induced oxidative stress relate to ferroptosis in rectal cancer?

Ionizing radiation generates reactive oxygen species and DNA damage, and oxidative stress can initiate lipid peroxidation. When lipid peroxide accumulation exceeds antioxidant capacity, this can trigger ferroptosis, an iron-dependent regulated cell death.

Why are ferroptosis-immune effects described as context-dependent?

Ferroptosis can enhance antitumor immunity when tumor-cell ferroptosis is favored, but non-selective lipid peroxidation may suppress dendritic-cell and CD8+ T-cell functions. The balance of these effects depends on the biological context.

How might ferroptosis targeting improve treatment outcomes in MSS/pMMR rectal cancer?

Ferroptosis-related biomarkers may improve response prediction in MSS/pMMR rectal cancer, particularly for patients considered for watch-and-wait. Tumor-selective ferroptosis may also help enhance radiotherapy and total neoadjuvant therapy alongside immune checkpoint blockade without compromising antitumor immunity.

Sep 22, 2026

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