Ferroptosis as an immunometabolic checkpoint in brain tumours: spatial vulnerabilities and therapeutic opportunities

Brain tumours, particularly glioblastoma, remain among the most lethal cancers due to considerable spatial variation, metabolic adaptability, immune suppression, and resistance to standard therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, presents a candidate target for new treatments in these tumours. This review examines ferroptosis as an immunometabolic checkpoint in brain tumours, emphasising how iron metabolism, glutathione depletion, lipid remodelling, and microenvironmental factors influence vulnerability across different regions. Using the SANRA framework, relevant studies from major sources were analysed to compile mechanistic, preclinical, and translational insights across glioblastoma and other brain tumour types. Evidence shows that brain tumours often activate ferroptosis-inhibiting pathways, including GPX4, SLC7A11, and NRF2, to promote survival, invasion, and therapy resistance. At the same time, recurrent or treatment-persistent tumour states may develop specific weaknesses to ferroptosis, especially in metabolically stressed or dormant cell populations. Ferroptosis interacts with immune responses: CD8 + T-cell-derived IFN-γ can trigger tumour ferroptosis, although this process may also foster immunosuppressive microenvironments depending on the context. Spatial heterogeneity adds complexity, as hypoxic tumour cores, invasive edges, and perivascular areas vary in oxidative stress, lipid metabolism, immune cell presence, and drug access. In conclusion, ferroptosis acts both as a tumour survival mechanism and as a potential vulnerability to target. Progress depends on integrating spatial and single-cell approaches, biomarker-driven patient stratification, and delivery methods that consider the blood-brain barrier to effectively and safely induce ferroptosis. This strategy highlights ferroptosis as a key focus for personalised neuro-oncology and combination therapy development.