Glioma-neuronal circuit remodeling induces regional immunosuppression
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.
Authors
- Saritha Krishna
- Jacob S. Young (ORCID: https://orcid.org/0000-0002-5499-4325)
- David Ronan Raleigh (ORCID: https://orcid.org/0000-0001-9299-8864)
- David Diebold (ORCID: https://orcid.org/0000-0002-6857-767X)
- Cathryn R. Cadwell (ORCID: https://orcid.org/0000-0003-1963-8285)
- Donovan L Baker (ORCID: https://orcid.org/0009-0008-6928-3252)
- Tiffany Chen (ORCID: https://orcid.org/0000-0003-2546-2941)
- Senthilnath Lakshmanachetty (ORCID: https://orcid.org/0000-0002-3760-2772)
- Shawn L. Hervey‐Jumper (ORCID: https://orcid.org/0000-0003-4699-260X)
- Payal Watchmaker (ORCID: https://orcid.org/0000-0002-0944-3890)
- Takahide Nejo (ORCID: https://orcid.org/0000-0002-9191-8823)
- Hideho Okada (ORCID: https://orcid.org/0000-0003-0076-9920)
- Andy Daniel (ORCID: https://orcid.org/0000-0002-3871-3685)
- Hirokazu Ogino (ORCID: https://orcid.org/0000-0002-2446-8789)
- Kevin Y. Lee (ORCID: https://orcid.org/0000-0002-1528-7417)
- Gabriella C. Maldonado (ORCID: https://orcid.org/0009-0007-2277-3070)
- Abrar Choudhury (ORCID: https://orcid.org/0000-0001-8312-2457)
- Akane Yamamichi (ORCID: https://orcid.org/0000-0002-8141-7339)
- Christian Jimenez
- Marco Gallus (ORCID: https://orcid.org/0009-0007-4954-8420)
- Kaori Okada
- Su Su Sabai Phyu
- Lan Phung
Institutions
- University of California, San Francisco (US)
- University Hospital Münster (DE)
- Parker Institute for Cancer Immunotherapy (US)
- Neurological Surgery (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1038/s41467-025-60074-z
- Citations
- 15
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 12.63