Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma

Lulu Cheng, Zezheng Fang, Junpeng Wang, Kaiyan Xi, Yi Zhang, Fan Feng, Le Yu, Myla Santiago, Jingjing Wang, Zimei Wu, Kang-nan Wang, Thomas Daubon, Shilei Ni (), Yanrong Zhang () and Yulin Zhang ()
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Lulu Cheng: Northwest A&F University
Zezheng Fang: Shandong University
Junpeng Wang: Shandong University
Kaiyan Xi: Shandong University
Yi Zhang: Shandong University
Fan Feng: Shandong University
Le Yu: Northwest University
Myla Santiago: University of Santo Tomas
Jingjing Wang: University of Auckland
Zimei Wu: University of Auckland
Kang-nan Wang: Shandong University
Thomas Daubon: CNRS
Shilei Ni: Shandong University
Yanrong Zhang: Northwest A&F University
Yulin Zhang: Shandong University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62244-5

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