ITLN1 suppresses colorectal cancer progression by orchestrating neutrophil maturation and spatial organization

Abstract Epithelial-derived intelectin-1 (ITLN1) is frequently downregulated in colorectal cancer, but whether it actively shapes anti-tumor immunity remains unclear. We integrate multiplex immunohistochemistry, spatial analysis, single-cell transcriptomics, chromatin-accessibility profiling, and perturbation models to define how ITLN1 regulates neutrophil maturation and spatial anti-tumor immunity. In treatment-naïve human colorectal cancer, higher ITLN1 expression associates with greater neutrophil infiltration, shorter distances between mature S100A9 + CXCR2 + neutrophils and ITLN1 + tumor epithelial cells, and improved survival. In mouse colorectal cancer models, Itln1 silencing accelerates tumor growth and metastasis, impairs CXCR2 + CD101 + mature neutrophil generation and tumor recruitment, and promotes LTF + S100A9 + immature neutrophil accumulation in hypoxic regions. Mechanistically, ITLN1 activates a JAK1/STAT3-associated C/EBPδ program that drives terminal granulopoiesis and CXCR2-dependent tumor homing, while recombinant ITLN1 restores neutrophil maturation and tumor-killing activity. Here, we reveal a cross-tissue ITLN1–STAT3/C/EBPδ–CXCR2 axis that links epithelial ITLN1 to bone marrow granulopoiesis, coordinating distal neutrophil maturation, mobilization and spatial organization in colorectal cancer.