Modulation of Ferroptosis Bridges Radiotherapy and Immunotherapy to Improve Cancer Treatment Outcomes

Programmed cell death evasion fuels malignant progression and undermines therapeutic efficacy across diverse neoplasms. Ferroptosis, an iron-driven membrane lipid oxidation that culminates in catastrophic membrane integrity loss, has emerged as a metabolically distinct liability amenable to therapeutic exploitation through radiotherapy and immunotherapy combinations. Ionizing radiation overwhelms cellular antioxidant buffering capacities within the tumour microenvironment, shifting the redox balance toward peroxidative membrane injury and bypassing resistance mechanisms active in treatment refractory tumours. Ferroptotic corpses release alarmins and lipid peroxidation products, triggering immunogenic cell death that reshapes immune surveillance, draws in antigen presenting cells, and reduces activation barriers for immune checkpoint inhibitors and adoptive cellular therapies. At the same time, radiotherapy triggered metabolic reprogramming of the tumour microenvironment marked by glutamine dependence, lipid peroxidation accumulation, and cystine limitation aligns with immunomodulatory effects to strengthen anti-tumour immunity. This Review deconstructs the enzymatic cascades and metabolic checkpoints that govern ferroptotic vulnerability, mapping how radiation induced metabolic rewiring links cytotoxic and immune stimulatory therapeutic goals. We examine whether ferroptosis serves as a central node connecting radiotherapy and immunotherapy, assessing preclinical data on radio immunotherapy combination strategies that leverage this dual functionality. Translational barriers remain. Constrained therapeutic windows, lack of validated pharmacodynamic markers, and unclear toxicological consequences in normal tissues require careful evaluation prior to clinical application. We outline a conceptual framework for deploying ferroptosis as a mechanistic bridge between radiotherapy and immunotherapy, suggesting that its targeted induction under tumour specific metabolic conditions could reshape multimodal treatment strategies and enhance cancer treatment outcomes beyond the marginal gains achievable with single agent approaches.