Ferroptosis reshapes the tumor immune microenvironment: molecular mechanisms, immune regulation, and therapeutic synergistic strategies

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(<i>GPX4</i>)axis and alternative pathways like Ferroptosis Suppressor Protein 1 (<i>FSP1</i>), 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 <i>NRF2, p53, and Hippo-YAP</i>, 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.