Microglial Fructose Metabolism Is Essential for Glioblastoma Growth

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

doi:10.1073/pnas.2521256123

Cancer BiologyProceedings of the National Academy of SciencesMar 17, 2026

Peer-reviewed journal article

Microglial Fructose Metabolism Is Essential for Glioblastoma Growth

Leah K. Billingham iD, Susan L DeLay, Yasmina Eshac iD, Tzu-Yi Chia, Shashwat Tripathi iD, Ian E Olson, Kaylee Zilinger iD, Jay Subbiah iD, Zhaoquan Wang iD, Nishanth S. Sadagopan iD, Hinda Najem iD, Guillaume Cognet iD, Joshua L. Katz iD, Ruochen Du iD, Khizar Rehan Nandoliya iD, Lauren K. Boland iD, Gustavo Ignacio Vázquez Cervantes iD, Si Wang iD, Hanxiao Wan, Allie B. Lipshutz iD, Alina R Murphy iD, Joseph T. Duffy iD, I. V. Balyasnikova iD, Peng Zhang iD, Dieter Henrik Heiland iD, , Jason M. Miska iD

Abstract

Glioblastoma (GBM) is most common and aggressive primary brain tumor in adults, for which standard of care hasnt changed in twenty years. GBM tumor associated macrophages (TAMCs), consisting of infiltrating myeloid cells from the periphery and resident microglia cells, are pro-tumorigenic, promoting tumor growth. Fructose is one of the most abundant metabolites in the GBM tumor microenvironment (TME), as well as in the healthy central nervous system (CNS). In the CNS and GBM, microglia are the predominant expressors of the fructose transporter GLUT5. Mice lacking the GLUT5 transporter (GLUT5-KO) survive significantly longer after orthotopic implantation of two glioma cell lines than wildtype mice, which is not due to dietary fructose or peripherally derived TAMCs. Investigation of the TME showed that GLUT5-KO mice have more highly activated and inflammatory innate and adaptive immune compartments. Microglia cultured in fructose have a decreased phagocytic ability and exhibit decreased inflammatory capacity due to the polyol pathway promoting redox homeostasis.

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