Ferroptosis at the tumor–immune interface: seeking a middle ground between tumor eradication and T-cell fitness

Abstract

Ferroptosis is an iron-dependent form of regulated cell death, which is manifested by the lethal accumulation of lipid peroxides. While it is considered a promising strategy for the elimination of apoptosis-resistant cancer cells, growing evidence highlights the dual role of ferroptosis within the tumor microenvironment (TME), affecting both cancer and immune cells. This review integrates tumor- and immune-cell ferroptosis within a three-layer framework comprising membrane lipid composition, antioxidant capacity, and microenvironmental pressure. We discuss how these layers interact to establish distinct ferroptosis thresholds across malignant and cytotoxic T-cell compartments. We highlight that cytotoxic CD8 + T cells and chimeric antigen receptor T cells may be particularly vulnerable to ferroptotic stress as a result of activation-induced metabolic reprogramming and the hostile, nutrient-deprived conditions of the TME. Furthermore, we discuss the immunomodulatory consequences of ferroptosis, including immunogenic and immunosuppressive mediators that can either ignite or stifle antitumor immunity. Lastly, we consider potential approaches that may leverage tumor ferroptosis while preserving T-cell function through tumor-directed ferroptosis induction and reinforcement of antioxidant defenses in engineered T cells. We propose that the ferroptosis axis may play a role in shaping the tumor–immune interface. Differential modulation of ferroptosis in tumor and immune cells could inform future strategies to address resistance to immune checkpoint blockade and improve the efficacy of adoptive cell therapies, although such approaches remain largely experimental and their clinical benefit has yet to be established.