Authors
Seok June Hong, Seheum Park, Sunghoon Kim, Young Il Park, Jun Seok Lee, Mikyung Kang, Jaewoong Lee, Martin Hemberg, Sung Eun Kim, Kwoneel Kim
Published in
Science advances. Volume 12. Issue 41. Pages eaeh2362. Oct 09, 2026. Epub Oct 07, 2026.
Abstract
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.
PMID:
42842645
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.
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