REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Ferroptosis Reshapes the Tumor Immune Microenvironment: Molecular Mechanisms, Immune Regulation, and Therapeutic Synergistic Strategies
Provisionally accepted
- Xinxiang Medical University, Xinxiang, China
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This article systematically reviews ferroptosis—an iron-dependent, lipid peroxidation-driven form of programmed cell death. It provides a detailed analysis of its core regulatory mechanisms, encompassing the drive from lipid peroxidation, the collapse of antioxidant defenses such as the glutathione peroxidase 4(GPX4)axis and alternative pathways like Ferroptosis Suppressor Protein 1 (FSP1), and the remodeling of iron and lipid metabolism. The interplay between ferroptosis and other cell death modalities, such as apoptosis and necroptosis, is also elucidated. The review focuses on the pivotal roles of key signaling pathways, including NRF2, p53, and Hippo-YAP, within the ferroptosis regulatory network. In the context of cancer therapy, the article emphasizes the potential of inducing ferroptosis for reversing drug resistance, inhibiting metastasis, and synergizing with immunotherapy. It systematically outlines direct induction strategies (e.g., small-molecule inducers, nanodelivery systems) and combination strategies with conventional therapies, targeted therapy, and immunotherapy. This review highlights that the bidirectional interplay between ferroptosis and the tumor immune microenvironment constitutes a novel therapeutic paradigm for combination therapy. Specifically, it elucidates how ferroptosis modulates immune cells such as CD8⁺ T cells and macrophages, reshaping the tumor immune microenvironment and offering new avenues for combination immunotherapy. We conclude by providing a roadmap for translating these insights into clinical practice, addressing current challenges, and outlining future directions for developing next-generation anticancer strategies.
Keywords: cancer therapy, ferroptosis, GPx4, Lipid Peroxidation, YAP Signaling Pathways
Received: 20 Dec 2025; Accepted: 10 Feb 2026.
Copyright: © 2026 Lv, Liu, Nie, Li, Kong, Shen, Jiao and Wang. 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:
Junna Jiao
Hui Wang
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