SLC39-driven zinc influx orchestrates pleiotropic tumor–immune crosstalk to establish an immune-suppressive microenvironment in colorectal cancer

Tumor metabolic reprogramming profoundly influences immune regulation, yet the mechanisms linking solute carrier (SLC) transporter activity to immune suppression remain elusive. Through integrative multi-omics, spatial, and single-cell analyses of colorectal cancer (CRC), we uncover a zinc influx–driven signaling axis mediated by the SLC39 family that establishes an immune-suppressive tumor ecosystem. Multi-omics clustering of 258 CRC patients identified three SLC-centered archetypes, among which an SLC39-enriched subtype displayed zinc pathway activation and correspondence to the “immune-desert” CMS2 subtype. Mechanistically, SLC39-mediated zinc influx activated the transcription factor CDX2, promoting enhancer-driven transcription of CD24, an anti-phagocytic “don’t eat me” signal. Zinc-dependent CD24 upregulation occurred independently of CD47 and was restricted to malignant epithelial cells. Single-cell and spatial transcriptomics revealed that CD24-expressing tumor cells interact with SIGLEC10 ⁺ monocyte-derived macrophages, dendritic cells, and resident macrophages, triggering pleiotropic immunoregulatory programs that suppress phagocytosis and remodel adhesion networks. This SLC39–CD24–SIGLEC10 axis defined spatially recurrent immune-suppressive niches and was associated with poor survival and resistance to immune checkpoint blockade. Functional assays confirmed that zinc-induced CD24–SIGLEC10 engagement attenuates macrophage phagocytosis, reversible by CD24 blockade. Furthermore, integrative modeling across five ICI-treated CRC cohorts demonstrated that a seven-gene signature encompassing SLC39 transporters, CDX2, CD24, and SIGLEC10 robustly predicted clinical response to immunotherapy, outperforming established biomarkers. These findings identify SLC39-mediated zinc influx as a regulator of tumor–immune crosstalk in CMS2-like CRC and highlight the SLC39–zinc–CD24–SIGLEC10 axis as a promising therapeutic target to overcome immune exclusion and immunotherapy resistance.