Glioma-neuronal circuit remodeling induces regional immunosuppression

Takahide Nejo, Saritha Krishna, Akane Yamamichi, Senthilnath Lakshmanachetty, Christian Jimenez, Kevin Y. Lee, Donovan L. Baker, Jacob S. Young, Tiffany Chen, Su Su Sabai Phyu, Lan Phung, Marco Gallus, Gabriella C. Maldonado, Kaori Okada, Hirokazu Ogino, Payal B. Watchmaker, David Diebold, Abrar Choudhury, Andy G. S. Daniel, Cathryn R. Cadwell, David R. Raleigh, Shawn L. Hervey-Jumper () and Hideho Okada ()
Additional contact information
Takahide Nejo: University of California, San Francisco
Saritha Krishna: University of California, San Francisco
Akane Yamamichi: University of California, San Francisco
Senthilnath Lakshmanachetty: University of California, San Francisco
Christian Jimenez: University of California, San Francisco
Kevin Y. Lee: University of California, San Francisco
Donovan L. Baker: University of California, San Francisco
Jacob S. Young: University of California, San Francisco
Tiffany Chen: University of California, San Francisco
Su Su Sabai Phyu: University of California, San Francisco
Lan Phung: University of California, San Francisco
Marco Gallus: University of California, San Francisco
Gabriella C. Maldonado: University of California, San Francisco
Kaori Okada: University of California, San Francisco
Hirokazu Ogino: University of California, San Francisco
Payal B. Watchmaker: University of California, San Francisco
David Diebold: University of California, San Francisco
Abrar Choudhury: University of California, San Francisco
Andy G. S. Daniel: University of California, San Francisco
Cathryn R. Cadwell: University of California, San Francisco
David R. Raleigh: University of California, San Francisco
Shawn L. Hervey-Jumper: University of California, San Francisco
Hideho Okada: University of California, San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Neuronal activity-driven mechanisms influence glioblastoma cell proliferation and invasion, while glioblastoma remodels neuronal circuits. Although a subpopulation of malignant cells enhances neuronal connectivity, their impact on the immune system remains unclear. Here, we show that glioblastoma regions with enhanced neuronal connectivity exhibit regional immunosuppression, characterized by distinct immune cell compositions and the enrichment of anti-inflammatory tumor-associated macrophages (TAMs). In preclinical models, knockout of Thrombospondin-1 (TSP1/Thbs1) in glioblastoma cells suppresses synaptogenesis and glutamatergic neuronal hyperexcitability. Furthermore, TSP1 knockout restores antigen presentation-related genes, promotes the infiltration of pro-inflammatory TAMs and CD8 + T-cells in the tumor, and alleviates TAM-mediated T-cell suppression. Pharmacological inhibition of glutamatergic signaling also shifts TAMs toward a less immunosuppressive state, prolongs survival in mice, and shows the potential to enhance the efficacy of immune cell-based therapy. These findings confirm that glioma-neuronal circuit remodeling is strongly linked with regional immunosuppression and suggest that targeting glioma-neuron-immune crosstalk could provide avenues for immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-60074-z

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