IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3

Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment. [Display omitted] •IRAK-M deficiency results in enhanced inflammation but diminished tumor growth•IRAK-M is induced in colon tumor cells due to combined Wnt and TLR activation•IRAK-M in tumor cells stabilizes STAT3 and enhances tumor barrier•IRAK-M expressed in tumor cells of CRC patients is associated with poor prognosis Kesselring et al. show that combined TLR and Wnt activation leads to IRAK-M expression in colorectal cancer cells, which is also associated with poor patient prognosis. Tumor cell-intrinsic IRAK-M regulates antimicrobial response and STAT3 stability, both promoting tumor progression.