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Updated: Mar 19, 2026
Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Microglial fructose metabolism is essential for glioblastoma growth
Leah K Billingham1,2, Susan L DeLay1,2, Yasmina Eshac1,2
1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
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.
Insights
Microglia utilize fructose for growth in glioblastoma (GBM). Blocking fructose metabolism via GLUT5 enhances anti-tumor immunity and slows GBM growth, offering a new therapeutic target.
Area of Science:
- Immunology
- Neuro-oncology
- Metabolic pathways
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with a complex immune microenvironment.
- Tumor-associated macrophages, including microglia, play a significant role in GBM's immune landscape.
- The metabolic reprogramming of myeloid cells in GBM is crucial, but microglial metabolism remains poorly understood.
Purpose of the Study:
- To investigate the role of microglial metabolism in the glioblastoma tumor microenvironment.
- To determine if fructose metabolism by microglia influences GBM progression and immune response.
- To explore GLUT5 as a potential therapeutic target for GBM immunotherapy.
Main Methods:
- Utilized murine orthotopic glioma and RCAS-derived tumor models.
- Examined fructose transporter GLUT5 expression in microglia within the GBM microenvironment.
- Assessed GBM growth and immune cell infiltration/activation in GLUT5-deficient mice.
Main Results:
- Microglia uniquely express GLUT5 and metabolize fructose within the GBM microenvironment.
- Global deletion of GLUT5 significantly inhibited GBM growth in mice, driven by microglial metabolic changes.
- GLUT5 deficiency led to increased innate and adaptive immune cell infiltration and activation, including enhanced antigen presentation and CD8+ T cell responses.
- Depletion of B-cells or CD8+ T cells abrogated the survival advantage in GLUT5-deficient mice, confirming GLUT5's role in suppressing adaptive immunity.
Conclusions:
- Microglial fructose metabolism, mediated by GLUT5, is a critical factor in immune suppression within the GBM microenvironment.
- Targeting microglial fructose metabolism presents a promising strategy to enhance anti-tumor immunity and improve therapeutic responses in glioblastoma.
