Reprogramming ferroptosis in MDSCs: For state-dependent immunotherapy combinations

Ferroptosis of myeloid-derived suppressor cells (MDSCs) exerts state-specific and contextually regulated effects on antitumor immunity. Sublethal ferroptotic stress is characterized by lipid peroxidation and the release of prostaglandin E₂ (PGE₂) and oxidized phospholipids. Such stress dampens T-cell and natural killer cell functions, reinforcing immunosuppression. Conversely, reducing intratumoral MDSC accumulation restores antitumor immunity. Disrupting metabolic pathways (e.g., the aconitate decarboxylase 1 (ACOD1)–itaconate–nuclear factor erythroid 2–related factor 2 (NRF2) axis) sensitizes tumor-infiltrating PMN-MDSCs to ferroptosis, while inhibiting N-acylsphingosine amidohydrolase 2 (ASAH2) drives lethal ferroptosis enhancing immune activation. This review proposes the “ferroptosis immunomodulation window” concept: (i) during sub-lethal ferroptotic stress, limitation/neutralization of MDSC-derived immunosuppressive lipid mediators, avoiding prolonged retention of cells in the phase; (ii) in a ferroptosis-resistant state, attenuating antioxidant/anti-ferroptotic defenses and inducing lethal ferroptosis to alleviate MDSC burden, while synergizing with immunotherapy. Future research should focus on developing delivery systems for the targeted control of MDSC ferroptosis. • In “cold” tumors, MDSCs are key immunosuppressors driving progression. • PMN-MDSCs within the TME undergo spontaneous ferroptosis. • Ferroptosis in MDSCs is state- and context-dependent, boosting or blunting immunity. • Phase-specific modulation of MDSC ferroptosis synergizes with immunotherapy.