Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance.

Abstract

Glioblastoma remains the most aggressive and treatment-resistant brain malignancy, driven by genetic heterogeneity, metabolic plasticity, and an immunosuppressive tumor microenvironment (TME). Current therapies rely on inducing tumor cell death through DNA damage; however, glioma stem cells (GSCs) upregulate compensatory DNA repair pathways, promoting resistance and tumor recurrence. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, offers a novel therapeutic strategy to overcome therapy resistance by exploiting glioblastoma's metabolic vulnerabilities. Unlike conventional therapies, ferroptosis bypasses DNA repair mechanisms, making it particularly effective against therapy-resistant GSCs. It reduces tumor growth by triggering iron-catalyzed oxidative stress, disrupting lipid metabolism, and pushing glioblastoma cells beyond their oxidative threshold. However, resistance mechanisms to ferroptosis, including iron metabolism regulators (IREB2 and ferritinophagy), lipid peroxidation enzymes (ACSL4 and ALOXs), and protective pathways (cystine transporters and glutathione peroxidase 4), limit its therapeutic potential. Extracellular vesicle-mediated iron transfer further contributes to ferroptosis resistance, fostering chemoresistance and radio-resistance. Beyond direct tumor killing, ferroptosis modulates the TME by releasing damage-associated molecular patterns, inducing reactive oxygen species, stimulating CD8⁺ T-cell activation, enhancing immune checkpoint blockade efficacy, and reprogramming tumor-associated macrophages toward an anti-tumor phenotype. Ferroptosis-based strategies, including glutathione peroxidase 4 inhibitors, nanoparticle-mediated iron delivery, and RNA-based therapies, offer promising avenues for enhancing glioblastoma treatment efficacy. This review highlights ferroptosis as a promising strategy for overcoming glioblastoma resistance by integrating it with chemotherapy, radiotherapy, and immunotherapy to enhance treatment efficacy. Given the complexity of glioblastoma, personalized ferroptosis-based approaches that address tumor heterogeneity, immune interactions, and metabolic adaptations are crucial for overcoming therapy resistance. Refining ferroptosis-targeted strategies by incorporating metabolic, immune, and genetic considerations can lead to more durable and effective therapies, ultimately transforming glioblastoma treatment and improving patient outcomes.