Lipid metabolism regulates ferroptosis and shapes immune checkpoint inhibitor response in cancer

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet primary and acquired resistance limit their durable clinical benefit. Ferroptosis, an iron-dependent form of cell death driven by phospholipid peroxidation, contributes to cluster of differentiation 8-positive (CD8 +) T-cell-mediated tumor control. Tumor cells may reduce their susceptibility to ferroptosis through lipid metabolic reprogramming, thereby limiting the efficacy of ICI-induced antitumor immunity. This review examines three major resistance-associated programs: reduced acyl-CoA synthetase long-chain family member 4 (ACSL4) activity, remodeling of the polyunsaturated fatty acid (PUFA)/monounsaturated fatty acid (MUFA) balance, and enhanced lipid peroxide detoxification mediated by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). It also discusses context-dependent immune effects, including ACSL4-associated restriction of immunogenic cell death (ICD) observed in melanoma models, ferroptotic vulnerability of CD8+ T cells, and heterogeneous responses among regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, dendritic cells, and natural killer cells. These findings suggest that future therapeutic strategies should avoid indiscriminate ferroptosis amplification and instead aim to selectively induce ferroptosis in tumor cells within a therapeutically effective range while preserving antitumor immune cells. This article reviews small-molecule drugs, nanodelivery systems, and dietary intervention strategies targeting this axis and analyzes the major challenges associated with clinical translation. Targeting ferroptosis may provide a rational approach to improving ICI responsiveness, provided that selectivity, immune-cell protection, and clinical validation are carefully addressed.