Narrative review demonstrates dual immune-activating and suppressive roles of ferroptosis in the tumor microenvironment, suggesting novel strategies to overcome immunotherapy resistance.
Ferroptosis, an iron-dependent form of programmed cell death, has recently garnered significant attention for its intricate involvement in the tumor immune microenvironment (TIME) and its implications in tumor immunotherapy. This review comprehensively explores the molecular mechanisms underlying ferroptosis and its regulation within tumor cells, highlighting the complex dual effects of ferroptosis on immune cell functions in TIME. While ferroptosis enhances cancer cell immunogenicity and promotes antitumor immunity through immune cell activation, it may also impair immune responses by disrupting T/B/NK cell functions and macrophage polarization. Critically, ferroptotic cells release damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and oxidized phospholipids, triggering inflammation via receptors like Toll-like receptor 4 (TLR4) and activating inflammasomes. This review explores how this ferroptosis-driven inflammatory cascade reshapes TIME components, highlighting its potential to sensitize tumors to immunotherapy. Targeting ferroptosis pathways may overcome resistance to immune checkpoint blockade. However, cancer cells develop ferroptosis resistance through metabolic adaptations and antioxidant systems, complicating therapeutic strategies. Future studies should unravel context-specific regulatory networks linking ferroptosis, inflammation, and immunity to optimize immunotherapy efficacy.
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Yang et al. (2026) studied this question.
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