Liposome modification THP boosts glioma ferroptosis and immunogenic cell death through reinforcement of mitochondrial dysfunction and mitophagy

Glioblastoma multiforme (GBM) is the most lethal tumor of the central nervous system, for which effective therapeutic options remain unavailable. Ferroptosis was a programmed cell death mechanism driven by lethal lipid peroxide accumulation, which emerged as a strategic target for glioma management. In this study, we show that phytochemical levo-tetrahydropalmatine (THP) activates ferroptosis and immunogenic cell death (ICD) though inducing mitochondrial dysfunction and augmented mitophagy. The significant improvement of the anti-tumor therapy efficacy for glioma through liposome modification THP (Lpo@THP NPs), delivering drugs through the blood-brain barrier (BBB). Lpo@THP NPs markedly suppressed GBM cell growth and impeded both migration and invasion in the murine glioma cell line GL261 as well as the human glioma cell line U87. Moreover, Lpo@THP NPs induced mitochondrial dysfunction and autophagy and further exerts its anti-GBM effects through lipid peroxidation and ferroptosis. Furthermore, ferroptosis initiation facilitates the release of damage-associated molecular patterns (DAMPs), thereby promoting ICD and enhancing the infiltration of cytotoxic T lymphocytes. In addition, both in vitro and in vivo studies confirmed that Lpo@THP NPs effectively suppressed GBM progression. Collectively, our findings establish immunomodulation of the tumor immune microenvironment (iTME) as a viable therapeutic approach to potentiate immunotherapy efficacy in glioma.