Ferroptosis in the tumor immune microenvironment: from danger signals to immune reprogramming

Immune-checkpoint blockade has changed cancer therapy, yet durable responses remain limited by immune exclusion, myeloid suppression and metabolic adaptation within the tumor immune microenvironment. Ferroptosis, an iron-dependent form of lipid-peroxidation-driven regulated cell death, offers a mechanistic bridge between tumor metabolism and antitumor immunity. Ferroptotic tumor cells can release danger signals, oxidized lipid mediators and antigenic material that shape dendritic-cell activation, macrophage behavior, myeloid-derived suppressor cell function and CD8+ T-cell responses. Based on currently heterogeneous evidence, we propose a working model in which acute and spatially restricted tumor-cell ferroptosis may favor immune priming and checkpoint sensitivity, whereas persistent or broadly distributed lipid-peroxidation stress may impair effector immune cells and sustain suppressive states. This temporal-spatial distinction remains incompletely validated in directly comparable experimental systems. This review summarizes the biochemical foundations of ferroptosis, the immune signals released by ferroptotic cells, the reprogramming of innate and adaptive immune compartments, and the emerging use of ferroptosis inducers, nanomedicines and immune-checkpoint combinations. We also discuss biomarkers, in vivo monitoring and immune-cell-specific toxicity as key barriers to clinical translation. A central conclusion is that ferroptosis should be treated not as a monolithic tumoricidal modality, but as a microenvironment-specific immune remodeling process whose therapeutic value depends on timing, localization and preservation of antitumor immune function.