SLC39-driven zinc influx orchestrates pleiotropic tumor–immune system cross-talk to establish immune suppression in colorectal cancer
Menée à partir de données multiomiques portant sur des échantillons tumoraux prélevés sur 258 patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel la surexpression du transporteur ionique SLC39 favorise l'immunosuppression via l'augmentation de la concentration intracellulaire du zinc, la surexpression de CD24 sur les cellules cancéreuses, l'interaction de cette protéine avec le récepteur SIGLEC10 des macrophages et l'inhibition de la phagocytose
Tumor metabolic programs shape immune evasion; however, the mechanism by which nutrient-transport systems rewire tumor-immune cell interactions remains unknown. We integrated bulk multi-omics, single-cell transcriptomics, spatial profiling, and functional assays for colorectal cancer–associated zinc-driven immunosuppressive circuit identification. Multi-omics analysis of 258 patients revealed three solute carrier transporter-centered archetypes, with an SLC39-enriched subtype aligned with consensus molecular subtype 2–like immune-desert tumors. SLC39-mediated zinc influx activated CDX2, which engaged a distal enhancer to induce tumor cell-specific CD24 expression. CD24+ tumor cells formed spatial niches with SIGLEC10-expressing monocyte-derived macrophages, dendritic cells, and resident macrophages, activating pleiotropic programs that suppress phagocytosis and remodel adhesion. SLC39 overexpression increased intracellular zinc and CD24 levels and reduced macrophage-mediated engulfment, whereas CD24 blockade restored phagocytosis. The zinc-CDX2-CD24-SIGLEC10 axis defined a terminal cancer cell state associated with poor survival and immune checkpoint blockade resistance. A seven-gene signature predicted immunotherapy responses across five colorectal cancer cohorts, identifying SLC39-driven zinc influx as a metabolic checkpoint governing immune exclusion.
Science Advances , article en libre accès, 2026