Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma

作者：Lulu Cheng, Z Fang, Junpeng Wang, Kaiyan Xi, Yi Zhang, Yi Zhang, Fan Feng, Le Yu, Myla R. Santiago-Bautista, Jingjing Wang, Zimei Wu, Kang‐Nan Wang, Thomas Daubon, Shilei Ni, Yulin Zhang, Yanrong Zhang, Yulin Zhang, Yulin Zhang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-62244-5 · 被引用次数：4 · 研究领域：Glioma Diagnosis and Treatment、Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism

Cellular and molecular heterogeneity contributes to the insufficient immunogenicity of glioblastoma multiforme (GBM), a lethal malignancy characterized by post-resection relapse, ultimately leading to limited immune cell infiltration. Here, we report a strategy to boost tumor immunity by activating the endogenous cGAS-STING signaling pathway through in-situ manipulation of the mitochondrial electron transport chain (ETC), thereby augmenting the immune responsiveness of GBM. Under white light irradiation, the synthetic butterfly-shaped photosensitizer B-TTPy disrupts the mitochondrial ETC by producing excessive reactive oxygen species. Synergistically, inhibition of checkpoint kinase 1 amplifies ETC dysfunction, thus enhancing the cytotoxicity of B-TTPy against tumor cells. Our results demonstrate that the in-house-customized Mitochondrial Electron Alteration Nanoparticles in Glioblastoma (MEANING) efficiently activate innate and adaptive immune response by recruiting antigen-presenting cells and cytotoxic T cells to the surgical margin. Moreover, biodegradable hydrogel-medicated surgical cavity treatment with MEANING can reshape the immunosuppressive tumor microenvironment and eliminate residual GBM cells. In sum, our findings establish a local immune activation approach for GBM, to prevent postoperative tumor recurrence and identify ETC blockade as a promising therapeutic strategy for low-immunogenic tumors. Cellular and molecular heterogeneity contributes to the insufficien...