Abstract

IL-10-signaling-deficiency-induced macrophage hyperactivation drives epithelial barrier disruption and severe colitis, but its role in colitis-associated colorectal cancer (CAC) remains unclear. Here, we report that macrophage-specific IL-10Rα deletion aggravates AOM-DSS-induced CAC in mice. These IL-10Rα-deficient macrophages exhibited a pro-inflammatory phenotype and secreted excessive IL-6 to stimulate intestinal epithelial cell (IEC) proliferation and tumorigenesis via the IL-6/p-STAT3 pathway. Genetic ablation or neutralization of macrophage-specific IL-6Rα reduced IEC p-STAT3 levels and tumor burden, whereas epithelial IL-6Rα deficiency or sgp130 treatment did not. IEC-BMDM co-culture and imaging flow cytometry identify a previously unrecognized macrophage-derived IL-6 trans-presentation as the dominant driver of IEC proliferation and tumorigenesis, rather than classical/trans-signaling. Targeting macrophage IL-6Rα in combination with PD-L1 blockage exerts complementary effects in CAC. Collectively, our data reveal that macrophage-specific IL-10 signaling protects against CAC by suppressing macrophage-dependent IL-6 trans-presentation, which drives excessive IEC proliferation and tumor development.