Ferroptosis at the intersection of radiotherapy and immunotherapy.

Immunotherapy and radiotherapy are widely used in the treatments of various cancers. However, their application remains limited in certain cancer types because only a small number of patients respond to monotherapy. Notably, these two modalities can exert synergistic anti-cancer effects when combined. A growing body of evidence suggests that ferroptosis plays a crucial role in such combination therapies. Specifically, immunotherapy-activated CD8+ T cells and radiotherapy-induced ataxia-telangiectasia mutated gene (ATM) activation (associated with DNA damage) can synergistically enhance tumor lipid oxidation and induce ferroptosis, primarily through the inhibition of SLC7A11. Thus, ferroptosis inducers are emerging as a promising strategy to improve the efficacy of combination therapies. This review outlines the role of ferroptosis in radio-immunotherapy and summarizes recent advances in the field, and proposes new therapeutic strategies and research directions for cancer treatment. Ferroptosis inducers could significantly improve the efficacy of combination therapies and hold great potential for clinical translation. Furthermore, different radiotherapy fractionation regimens induce varying degrees of ferroptosis. Increasing single-fraction radiation doses can enhance lipid peroxidation and ferroptosis, suggesting a promising research direction for combining hypofractionation radiotherapy with ferroptosis inducers (FINs).