AbstractBackground. Cancer immunotherapy with engineered T cells has become a standard treatment for certain haematological cancers. However, clinical tria

Glycolysis-dependent T cell function is hindered by glucose scarcity in the tumour microenvironment. Now in Cancer Cell, Schild et al. engineered T cells to utilize fructose via GLUT5, enhancing their metabolic activity and cytotoxicity.

Glycolysis-dependent T cell function is hindered by glucose scarcity in the tumour microenvironment. Now in Cancer Cell, Schild et al. engineered T cells to utilize fructose via GLUT5, enhancing their...

In mammals, glucose transporters (GLUT) control organism-wide blood-glucose homeostasis. In human, this is accomplished by 14 different GLUT isoforms, that transport glucose and other monosaccharides with varying substrate preferences and kinetics. Nevertheless, there is little difference between th

Nature Reviews Cancer, Published online: 27 March 2025; doi:10.1038/s41568-025-00813-yGlycolysis-dependent T cell function is hindered by glucose scarcity in the tumour microenvironment. Now in Cancer Cell, Schild et al. engineered T cells to utilize fructose via GLUT5, enhancing their metabolic activity and cytotoxicity.

Glucose deprivation in the primary CNS lymphoma (PCNSL) tumor microenvironment drives SLC2A5 (encoding GLUT5)-dependent fructose metabolism in tumor cells, while hypoxia induces HIF-mediated SLC2A5 expression in tumor-supportive macrophages, revealing SLC2A5 -driven fructose utilization as a shared and targetable metabolic vulnerability across malignant and microenvironmental compartments. ABSTRACT Primary central nervous system lymphoma (PCNSL) exhibits distinct molecular features and a unique tumor microenvironment (TME) characterized by hypoxia and reduced cerebrospinal fluid glucose levels. However, the extent to which the PCNSL TME shapes the metabolic and functional states of tumor and non-tumor microenvironment cells remains largely unexplored. Utilizing single-cell multi-omic approaches, we systematically dissected tumor-TME interactions in PCNSL and showed that glucose deprivation within the TME leads to enhanced SLC2A5 -mediated fructose metabolism in tumor cells and contributes to T cell dysfunction. Furthermore, hypoxia within the TME induces SLC2A5 expression in tumor-supportive macrophages through HIF-dependent transcriptional regulation, establishing SLC2A5 and its associated fructose metabolism as potential metabolic vulnerabilities in both tumor cells and tumor-supportive macrophages. In vitro and in vivo functional assays further demonstrated that genetic and pharmacologic inhibition of SLC2A5 -mediated fructose uptake markedly suppressed lymphoma growth. Collectively, our study uncovers a novel potential metabolic liability targeting tumor–TME interactions in PCNSL.