Abstract Background: Glioblastoma (GBM) is the most aggressive primary brain tumor, with limited therapeutic options due to metabolic adaptability and resistance to cell death. Ferroptosis, an iron-dependent pathway involving lipid peroxidation, offers a promising GBM target. Extracellular vesicle (EV)-based mitochondrial transfer enables intercellular shuttling of damaged mitochondria, modulating recipient cell metabolism in cancer microenvironments. During adipocyte thermogenesis, damaged mitochondria are released as Mito-EVs under stress conditions like obesity. This study explores how Mito-EV-mediated transfer from stressed adipocytes activates ferroptosis in GBM cells. Methods: Mito-EVs containing stressed mitochondria were isolated from adipocytes via centrifugation and characterized by microscopy and protein analysis. GBM cells were exposed to Mito-EVs for mitochondrial transfer, compared to free mitochondria, and confirmed by imaging. Ferroptosis was induced with activators and evaluated through cell death and stress markers. In vivo, circulating Mito-EVs from an obese mouse model were injected into GBM tumor models, alone or with ferroptosis agents, with tumor response assessed by imaging and tissue analysis. Results: Mito-EV transfer enhanced mitochondrial uptake in GBM cells over free mitochondria, integrating into networks and inducing oxidative stress. This increased ferroptosis sensitivity, with reduced activator requirements and altered cell death regulators. In vivo, Mito-EV treatment promoted ferroptosis and, when combined with activators, reduced tumor growth with ferroptosis evidence and low toxicity. Conclusions: Mito-EV-mediated mitochondrial transfer from stressed adipocytes boosts ferroptosis in GBM via oxidative stress, proposing a new strategy using circulating Mito-EVs for anticancer effects in obesity-linked contexts. Citation Format: Junbo Liao, Shuhan Cao, Ka Kit Gilberto Leung, Karrie. M Kiang. Mito-EV-driven mitochondrial transfer: A trigger for ferroptosis in glioblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3342.
Liao et al. (Fri,) studied this question.