Iron-fueled ferroptosis - a new axis for immunomodulation to overcome cancer drug resistance - from immune microenvironment crosstalk to therapeutic translation

Sep 22, 2026

Resistance to chemotherapy and targeted therapy in cancer often arises from apoptosis evasion, whereas ferroptosis—iron-dependent regulated cell death driven by lipid peroxidation—provides a promising alternative. The tumor immune microenvironment governs ferroptosis susceptibility through signaling from CD8+ T cells and other immune populations such as Tregs, MDSCs, and macrophages. Inducing ferroptosis promotes immunogenic cell death, boosts T-cell infiltration, and can synergize with immune checkpoint blockade. This review covers molecular sensitivity, immune-ferroptosis crosstalk, combination approaches, and barriers to clinical translation including toxicity and patient stratification.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages33

Reading Time1 h 23 min

AccessFree to download

1 Introduction

1.1 Clinical background

1.2 The unique signiﬁcance of ferroptosis

TYPE Review PUBLISHED 13 January 2026 DOI 10.3389/fimmu.2025.1726210 OPEN ACCESS EDITED BY Titto Augustine, Purdue University Indianapolis, United States REVIEWED BY Ran Tao, Texas A&M University Baylor College of Dentistry, United States Fangmin Zhong, Nanchang University, China Tengfei Liu, Shanghai Jiao Tong University, China Hailiang Wang, Qingdao University, China Fuwen Yao, Stanford University, United States Afrasim Moin, University of Hail, Saudi Arabia Xiao Wei, Chengdu University, China *CORRESPONDENCE Ruipei Chen [329082694@qq.com](329082694@qq.com)[ ](329082694@qq.com)Hongpeng Chen [380260714@qq.com](380260714@qq.com)[ ](380260714@qq.com)Junbing He [junbingg@gdmu.edu.cn](junbingg@gdmu.edu.cn) †These authors have contributed equally to this work RECEIVED 16 October 2025 REVISED 02 November 2025 ACCEPTED 22 December 2025 PUBLISHED 13 January 2026 CITATION Wu Y, Zhang K, Jiang N, Chen Z, Sun X, Zha H, Lin M, Li J, Pan X, Chen J, He J, Chen H and Chen R (2026) Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation. Front. Immunol. 16:1726210 . doi: 10.3389/fimmu.2025.1726210 COPYRIGHT © 2026 Wu, Zhang, Jiang, Chen, Sun, Zha, Lin, Li, Pan, Chen, He, Chen and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation Yimao Wu 1,2†, Kaiyu Zhang 3†, Naijun Jiang 4†, Zichang Chen 2†, Xiaojing Sun 5, Hongyu Zha 3, Mingjun Lin 3, Jingxin Li 3, Xiaocheng Pan 6, Jiadong Chen 6, Junbing He 7*, Hongpeng Chen 1* and Ruipei Chen 1* 1Oncology, Jieyang People’s Hospital, Jieyang, China, 2Second Clinical Medical College, Guangdong Medical University, Dongguan, China, 3Second Clinical Medical College, Anhui Medical University, HeFei, China, 4 First Clinical Medical College, Anhui Medical University, Hefei, China, 5 Fourth Clinical Medical College, Anhui Medical University, Hefei, China, 6Jieyang People’s Hospital, Jieyang, China, 7Jieyang Medical Research Center, Jieyang People’s Hospital, Jieyang, China Resistance to chemotherapy and targeted therapy in cancer is largely due to evasion of apoptosis, but ferroptosis—an iron-dependent form of regulated cell death driven by lipid peroxidation—offers a promising alternative, particularly in aggressive and therapy-resistant subtypes. The tumor immune microenvironment plays a central role in modulating ferroptosis susceptibility: CD8+ T cell-derived IFNg downregulates system Xc-and upregulates ACSL4, while other immune cells such as Tregs, MDSCs, and macrophages further ﬁne-tune ferroptosis through cytokine and redox signaling. Importantly, ferroptosis induction promotes immunogenic cell death, enhancing T cell inﬁltration and synergizing with immune checkpoint blockade to achieve sustained antitumor immunity. This review delineates the molecular basis of ferroptosis sensitivity in resistant cancers, explores immune-ferroptosis crosstalk, evaluates combination strategies with immunotherapy, and discusses challenges such as toxicity and patient stratiﬁcation to advance clinical translation. KEYWORDS ferroptosis, cancer drug resistance, antitumor immunity, tumor microenvironment, immunotherapy, lipid peroxidation Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) 1 Introduction 1.1 Clinical background In cancer therapy, the development of drug resista

FAQs

Why does cancer drug resistance limit chemotherapy and targeted therapy effectiveness?

Cancer cells often develop resistance by evading therapy-induced death signals, including apoptosis evasion through anti-apoptotic proteins or mutations in apoptosis-related genes.

What biological mechanism makes ferroptosis relevant to overcoming drug resistance?

Ferroptosis is iron-dependent and triggered by lipid peroxidation accumulation, and resistant cancers may show metabolic and antioxidant defects that create selective vulnerability.

How does the tumor immune microenvironment influence ferroptosis susceptibility?

Immune cells modulate ferroptosis via cytokine and redox signaling; for example, CD8+ T cell-derived IFN-γ can downregulate system Xc- and upregulate ACSL4, while other immune populations further tune ferroptosis.

Sep 22, 2026

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