Microglial fructose metabolism is essential for glioblastoma growth

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-03-17
DOI
https://doi.org/10.1073/pnas.2521256123
Primary Topic
Diet, Metabolism, and Disease
Type
article
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article

Microglial fructose metabolism is essential for glioblastoma growth

Gustavo Ignacio Vázquez Cervantes, Shashwat Tripathi, Guillaume Cognet, Nishanth S. Sadagopan et al.
Proceedings of the National Academy of Sciences
Diet, Metabolism, and Disease
article

Microglial fructose metabolism is essential for glioblastoma growth

Gustavo Ignacio Vázquez Cervantes, Shashwat Tripathi, Guillaume Cognet, Nishanth S. Sadagopan, Allie Lipshutz, Zhaoquan Wang, Joshua L. Katz, Lauren Boland, Alina R Murphy, Tzu-Yi Chia, Navdeep S. Chandel, Hanxiao Wan, Khizar Rehan Nandoliya, Justin S. A Perry, Joseph Duffy, I. V. Balyasnikova, Dieter Henrik Heiland, Jason Miska, Amy B. Heimberger, Ruochen Du, Kaylee Zilinger, Susan L DeLay, Jay Subbiah, Yasmina Eshac, Catalina Lee-Chang, Hinda Najem, Si Wang, Alexander Muir, Peng Zhang, Leah K. Billingham, Ian E Olson, Atique U. Ahmed
article en

Abstract

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

Proceedings of the National Academy of SciencesVol. 123(12)
Memorial Sloan Kettering Cancer Center (US), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Cornell University (US), University Medical Center Freiburg (DE), University of Chicago (US), Universitätsklinikum Erlangen (DE), German Marine Research Consortium (DE), Comprehensive Cancer Center Erlangen (DE), Neurological Surgery (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University
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Diet, Metabolism, and Disease
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