Single‐Cell Profiling Identifies SLC2A5 ‐Mediated Fructose Metabolism as a Vulnerability in Primary CNS Lymphoma

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.