Ferroptosis and metabolic reprogramming in the immunosuppressive microenvironment of glioblastoma: emerging mechanisms and novel strategies

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM often exhibits resistance to conventional apoptosis-inducing therapies, and its immunosuppressive microenvironment limits the efficacy of existing treatments. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of cell death. The unique metabolic reprogramming in GBM, including dysregulated iron metabolism, abnormal lipid metabolism, and imbalanced antioxidant defenses, collectively determines the susceptibility of tumor cells to ferroptosis. There is a bidirectional regulatory relationship between ferroptosis and the tumor immune microenvironment (TIME). Ferroptosis can release damage-associated molecular patterns and activate dendritic cells, thereby enhancing antitumor immunity. Simultaneously, the functional state of immune cells directly influences the progression of ferroptosis. Targeting ferroptosis can enhance the efficacy of temozolomide (TMZ) and increase radiosensitivity. Nanodelivery systems can overcome blood-brain barrier limitations, enabling the co-delivery of ferroptosis inducers and immunomodulators. The combination of ferroptosis with immune checkpoint blockade can reverse the suppressive TIME. This review systematically summarizes the mechanisms by which ferroptosis regulates the suppressive TIME of GBM; the application of ferroptosis-targeting strategies (including ferroptosis inducers, immunotherapy, and targeted nanomaterials) in GBM treatment; and prospects for clinical translation. Targeting ferroptosis provides a new direction for modulating the suppressive TIME of GBM and developing novel therapeutic strategies for GBM.