Ferroptosis-induced immune modulation: a new frontier in glioblastoma therapy

Glioblastoma multiforme (GBM) remains the most aggressive and treatment-refractory brain tumor, largely due to its heterogeneity and immunosuppressive microenvironment. Recent discoveries have highlighted a compelling strategy to overcome GBM resistance mechanisms using ferroptosis, an iron-dependent, non-apoptotic type of regulated cell death marked by lipid peroxidation. This review systematically explores the molecular regulators of ferroptosis, including GPX4, SLCA11, ACSL4, and iron metabolism pathways that dictate susceptibility to oxidative damage. The integration of ferroptosis with immune checkpoint inhibition and conventional modalities such as radiotherapy and chemotherapy demonstrated synergistic sensitization of tumor cells while enhancing antitumor immune responses. Ferroptosis induces immunogenic damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP release, promoting dendritic cell maturation, macrophage repolarization, and CD8⁺ cell infiltration, transforming the "cold" GBM milieu into an immunogenic microenvironment. Emerging nanotechnology-based ferroptosis inducers (FINs), including iron oxide nanoparticles and liposomal formulations, further optimize drug delivery across the blood-brain barrier while reducing systemic toxicity. Moreover, the regulation of ferroptosis by non-coding RNAs provides an additional avenue for therapeutic modulation through immunotherapy and redox-modulating strategies, offering a transformative direction in GBM management and redefining treatment beyond apoptosis resistance toward precision immunometabolic targeting.