Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma

• Published in: Nature communications Vol. 16; no. 1; pp. 6946 - 15
• Main Authors: Cheng, Lulu, Fang, Zezheng, Wang, Junpeng, Xi, Kaiyan, Zhang, Yi, Feng, Fan, Yu, Le, Santiago, Myla, Wang, Jingjing, Wu, Zimei, Wang, Kang-nan, Daubon, Thomas, Ni, Shilei, Zhang, Yanrong, Zhang, Yulin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/19; 14/28; 14/34; 38/1; 38/5; 38/77; 38/89; 631/61/350/354; 631/67/1922; 631/67/580; 64/60; Adaptive immunity; Adaptive Immunity - drug effects; Animals; Antigen-presenting cells; Biodegradation; Brain cancer; Brain Neoplasms - immunology; Brain Neoplasms - surgery; Cell cycle; Cell Line, Tumor; Cytotoxicity; Electron transport; Electron transport chain; Female; Genes; Glioblastoma; Glioblastoma - immunology; Glioblastoma - pathology; Glioblastoma - surgery; Glioblastoma - therapy; Glioma; Heterogeneity; Humanities and Social Sciences; Humans; Hydrogels; Immune response; Immune system; Immunogenicity; Infiltration; Irradiation; Kinases; Light; Light irradiation; Lymphocytes; Lymphocytes T; Malignancy; Medical prognosis; Metabolism; Metastases; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - immunology; Mitochondria - metabolism; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - prevention & control; Photosensitizing Agents - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumor cells; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors; White light
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-62244-5

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 insufficient immunogenicity of glioblastoma (GBM), ultimately leading to limited immune cell infiltration. Here this group reports a GBM therapeutic strategy by activating endogenous cGAS-STING signaling pathway by modulating mitochondrial electron transport chain thereby augmenting the immune responsiveness of GBM.