KLF5-SLC2A1 axis promotes intrahepatic cholangiocarcinoma progression via SPP1 + macrophage-mediated microenvironment remodeling

Tumor metabolic reprogramming shapes the tumor microenvironment (TME) and modulates anti-tumor immunity, yet the interplay between metabolic adaptation and immune regulation in intrahepatic cholangiocarcinoma (ICC) remains unclear. We investigated the role of the glucose transporter GLUT1 (SLC2A1) as a potential immunometabolic regulator in ICC. We integrated bulk and single-cell transcriptomics with multi-omics profiling, and performed in vitro and in vivo functional validation. Pharmacologic inhibition was achieved using the selective GLUT1 inhibitor BAY-876. Single-cell analyses and tumor cell–macrophage co-culture assays were used to characterize immune composition and macrophage polarization. Mechanistic studies probed signaling pathways linking glucose transport to cytokine release and macrophage activation. GLUT1 expression was increased in malignant cholangiocytes and associated with worse prognosis. Single-cell data revealed stage-dependent GLUT1 dynamics, peaking at intermediate tumor states and declining during late-stage metabolic shifts toward lipid and MYC-driven programs. BAY-876 suppressed tumor cell proliferation and reduced tumor burden in preclinical models. High GLUT1 abundance correlated with an immune-suppressed TME reduced overall immune infiltration and predominance of M2-like macrophages, whereas GLUT1 inhibition increased tumor cell release of TNFα, activated NF-κB signaling in macrophages, and promoted M1-like polarization. Mechanistically, GLUT1 blockade activated p53 signaling and enhanced ADAM17 maturation, facilitating proteolytic release of TNFα and thereby engaging a p53/ADAM17/TNFα/NF-κB axis that links glucose transport to macrophage phenotype. These data nominate GLUT1 as an immunometabolic regulator in ICC and provide a rationale to evaluate GLUT1-directed strategies, alone or combined with immune-modulatory agents, to overcome metabolic heterogeneity and remodel the TME.