Myeloid-derived IL6/JAK/STAT3 signaling establishes a spatially organized immunosuppressive niche to fuel colitis-associated carcinogenesis

Chronic inflammation drives the malignant transformation of colitis, yet the underlying mechanisms remain incompletely understood. IL6/JAK/STAT3 axis has been implicated in inflammation-associated cancer, but its precise cellular sources, spatial organization, and functional dynamics during colitis-associated carcinogenesis (CAC) require systematic investigation. DSS-induced colitis and AOM/DSS-induced CAC models were established in wild-type and Apc Min/+ mice, assessed with survival and histological analysis. Multi-omics approaches, including bulk RNA-seq ( n = 5 samples per group), time-series RNA-seq (3 per time point per group), single-cell RNA-seq (3 per group), and spatial transcriptomics (1 per group), were employed to profile transcriptomic kinetics and cellular heterogeneity. IL6 knockout mice were utilized to validate the functional role of IL6. Colonoscopy, histology, and immune infiltration analyses were performed to assess disease severity and tumor burden. Single-cell transcriptomic profiling reveals a coordinated remodeling of the immune landscape during CAC progression, characterized by M2 macrophage polarization and expansion of regulatory T and B cell subsets. IL6 exhibits stage-dependent duality. It is essential for mucosal protection during acute colitis, yet its sustained expression from M2-polarized macrophages and stromal cells in the chronic phase drives persistent JAK/STAT3 activation. Spatial transcriptomics identifies a distinct myeloid-enriched niche co-localized with proliferative epithelium, physically coupling IL6 sources with tumor-initiating compartments. IL6 ablation in mice exacerbates acute colitis but paradoxically attenuates tumor development in CAC, confirming its pathogenic role in carcinogenesis. These findings establish the myeloid-derived IL6/JAK/STAT3 axis as a major regulator that orchestrates an immunosuppressive microenvironment and fuels the transition from colitis to colorectal cancer. This axis represents a potential therapeutic target for preventing malignant progression in inflammatory bowel disease.