Biological Sciences Division
Published March 17, 2026 | Version v1
Journal article Open

Microglial fructose metabolism is essential for glioblastoma growth

Creators

  • 1. Northwestern University
  • 2. Memorial Sloan Kettering Cancer Center
  • 3. University of Chicago
  • 4. Cornell University
  • 5. University of Freiburg

Description

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.

Data availability

The single-cell RNA-sequencing data generated in this study have been deposited in the publicly accessible NCBI Gene Expression Omnibus (GEO) under accession number: GSE296335 (75). All other data supporting the findings of this study are included within the manuscript and its supporting information.

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billingham-et-al-2026-microglial-fructose-metabolism-is-essential-for-glioblastoma-growth.pdf

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Additional details

Identifiers

DOI
10.1073/pnas.2521256123
Other
oai:uchicago.tind.io:16855

Funding

National Cancer Institute
5R01CA279686-03
National Cancer Institute
P50CA221747
National Cancer Institute
T32CA070085
National Cancer Institute
R37CA258426
Cancer Research Institute
CR68036
Cancer Research Institute
CR13733
National Institute of Neurological Disorders and Stroke
R01NS122395
National Institute of General Medical Sciences
1DP2GM146337
National Institute of Allergy and Infectious Diseases
5T32AI134632
National Institute of Neurological Disorders and Stroke
NS120547
National Cancer Institute
P30CA060553

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Ben May Department for Cancer Research