REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicTumor-Associated Macrophages and Tumor-Infiltrating Lymphocytes in the Tumor MicroenvironmentView all 16 articles
Immunometabolic Crosstalk Between Tumor-Associated Macrophages and Ferroptotic Cancer Cells: Mechanisms, Regulation, and Therapeutic Applications
Provisionally accepted
- 1Hubei University of Chinese Medicine, Wuhan, China
- 2Wangjing Hospital, beijing, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Tumor-associated macrophages (TAMs) are central regulators of the metabolic and immunological landscape of solid tumors and are increasingly recognized as key determinants of cancer-cell susceptibility to ferroptosis. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, is tightly shaped by metabolic cues within the tumor microenvironment (TME). TAMs, through their remarkable metabolic plasticity, modulate iron flux, redox balance, polyunsaturated fatty-acid (PUFA) availability, and glutathione-dependent antioxidant pathways, each of which directly influences ferroptotic vulnerability in neighboring tumor cells. In this review, we synthesize current evidence linking TAM polarization states to the regulation of ferroptosis-related processes, including lipid remodeling, cystokine metabolism, reactive oxygen species (ROS) buffering, and immunometabolic signaling. We further discuss how TAM-derived cytokines, lipid mediators, and iron-handling proteins orchestrate a microenvironment that either promotes or restrains ferroptotic cell death. Finally, we highlight emerging therapeutic strategies aimed at rewiring TAM metabolism or exploiting ferroptosis to overcome immune suppression and therapy resistance. By integrating immunological and metabolic dimensions, this review provides a framework for understanding TAM-ferroptosis crosstalk and its implications for precision immunotherapy in cancer.
Keywords: cancer therapy, ferroptosis, Immunometabolism, iron homeostasis, redox signaling, Tumor-associated macrophages
Received: 13 May 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 QIAN, Bai, Li, Rao, Huang, Liu, Wei and Zhang. 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) or licensor 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.
* Correspondence:
Wei Wei
Zhuo Zhang
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.