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Peer-reviewedCC BYScience Advances

SLC39-driven zinc influx orchestrates pleiotropic tumor–immune system cross-talk to establish immune suppression in colorectal cancer

  • Seok June Hong1
  • Seheum Park2,3,4
  • Sunghoon Kim2,3,4
  • Young Il Park2
  • Jun Seok Lee5
  • Mikyung Kang6,7,8
  • Jaewoong Lee2,3,9,10
  • Martin Hemberg11
  • Sung Eun Kim2,3,8
  • Kwoneel Kim1,12
12 affiliations
  1. 1Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea.
  2. 2School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul 02841, Republic of Korea.
  3. 3Department of Integrated Biomedical and Life Sciences, College of Health Sciences, Korea University, Seoul 02841, Republic of Korea.
  4. 4L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul 02841, Republic of Korea.
  5. 5Department of Health and Safety Convergence Science, College of Health Sciences, Korea University, Seoul 02841, Republic of Korea.
  6. 6School of Health and Environmental Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea.
  7. 7Department of Health and Safety Convergence Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea.
  8. 8Biomedical Research Center, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
  9. 9Interdisciplinary Program in Precision Public Health, Korea University, Seoul 02841, Republic of Korea.
  10. 10Center of Molecular and Cellular Oncology, Yale University, New Haven, CT 06511, USA.
  11. 11Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02115, USA.
  12. 12Department of Biology, Kyung Hee University, Seoul, Republic of Korea.
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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.

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Cite

BibTeXRIS
BibTeX
@article{hong2026slc39driven,
  title = {{SLC39-driven zinc influx orchestrates pleiotropic tumor–immune system cross-talk to establish immune suppression in colorectal cancer}},
  author = {Seok June Hong and Seheum Park and Sunghoon Kim and Young Il Park and Jun Seok Lee and Mikyung Kang and Jaewoong Lee and Martin Hemberg and Sung Eun Kim and Kwoneel Kim},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeh2362},
  url = {https://www.science.org/doi/10.1126/sciadv.aeh2362},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - SLC39-driven zinc influx orchestrates pleiotropic tumor–immune system cross-talk to establish immune suppression in colorectal cancer
AU  - Seok June Hong
AU  - Seheum Park
AU  - Sunghoon Kim
AU  - Young Il Park
AU  - Jun Seok Lee
AU  - Mikyung Kang
AU  - Jaewoong Lee
AU  - Martin Hemberg
AU  - Sung Eun Kim
AU  - Kwoneel Kim
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeh2362
UR  - https://www.science.org/doi/10.1126/sciadv.aeh2362
AB  - 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.
SN  - 2375-2548
ER  -