Microglial fructose metabolism is essential for glioblastoma growth
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (32)
Leah K. Billingham
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Susan L. DeLay
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Yasmina Eshac
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Tzu-Yi Chia
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Shashwat Tripathi
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Ian E Olson
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Kaylee Zilinger
Department of Cellular & Molecular Physiology, Yale University
Jay Subbiah
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Zhaoquan Wang
Nishanth S. Sadagopan
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Hinda Najem
Guillaume Cognet
Joshua L. Katz
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Ruochen Du
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Khizar R. Nandoliya
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Lauren K. Boland
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Gustavo Ignacio Vázquez-Cervantes
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Si Wang
Hanxiao Wan
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Allie B. Lipshutz
Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine
Alina R Murphy
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Joseph Duffy
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Irina V. Balyasnikova
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Peng Zhang
Dieter Henrik Heiland
Atique U. Ahmed
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Catalina Lee-Chang
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Amy B. Heimberger
Justin S. A. Perry
Alexander Muir
Navdeep S. Chandel
Jason Miska
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University