Ferroptosis-driven radio-immunosensitization: an emerging mechanistic framework for enhancing response to immune...

Immune checkpoint inhibitors (ICIs) provide durable tumor control in some patients, but resistance can develop through tumor-intrinsic and microenvironmental mechanisms. This narrative review examines the metabolic and immune conditions under which ferroptosis may enhance ICI responsiveness or resensitize selected ICI-refractory tumors. Radiotherapy (RT) increases oxidizable phospholipids and can repress SLC7A11, the light-chain component of system xc^-. ICI-activated CD8⁺ T cells provide convergent interferon-γ signaling. Tumors can resist this pressure through GPX4, FSP1-CoQ10, mitochondrial DHODH, NRF2-dependent programs, and iron-export pathways. Recent preclinical studies have tested RT with ferroptosis-directed interventions and ICIs. These studies include functional evidence of ferroptosis dependence in radioresistant lung cancer and resensitization of LKB1-deficient, primarily ICI-refractory tumors. The findings support a preclinical rationale for combination therapy, although their causal strength varies. Reversal of clinically defined acquired ICI resistance remains unestablished, and the clinical RT-ICI studies reviewed here did not measure ferroptosis in patients. The immune effects also vary by cell type. Tumor-cell ferroptosis may support immunity, whereas lipid peroxidation in CD8⁺ T cells, dendritic cells, or polymorphonuclear myeloid-derived suppressor cells can impair antitumor responses. Translation will require functional validation, cell-resolved biomarkers, achievable drug exposures, and evaluation of RT dose, fractionation, and sequence alongside normal-tissue and immune-cell safety.