Smad4 Deficiency in S100A4+ Macrophages Enhances Colitis-associated Tumorigenesis by Promoting Macrophage Lipid Metabolism Augmented M2 Polarization.

S100A4 is primarily expressed in intestinal macrophages, and promotes colonic inflammation and colitis-associated colon tumorigenesis. Smad4 is also expressed in the colon; however, it inhibits colitis-associated cancer (CAC) development. The specific role of Smad4 in S100A4⁺ cells in CAC remains unknown. In this study, an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model was established in mice with S100A4⁺ cell-specific Smad4 deletion (S100A4 ^Smad4-/-). Smad4 deficiency in S100A4⁺ cells exacerbated DSS-induced colitis and promoted colorectal tumorigenesis. In addition, S100A4⁺ cell-specific Smad4 ablation promoted the M2 polarization of macrophages in CAC. Mechanistically, Smad4 depletion in macrophages enhanced lipid metabolism by activating the FA binding protein 2 (Fabp2)/STAT6 pathway. Furthermore, Smad4 deficiency in macrophages promoted MC38 tumor growth in myeloid-specific Smad4 deficient (Lyz ^Smad4-/-) mice, whereas blocking Fabp2 expression reversed the tumor growth. Additionally, high Smad4 expression was associated with prolonged survival in patients with colorectal cancer. Thus, Smad4 in S100A4⁺ macrophages plays a tumor-inhibiting role in CAC development and supports its use as a prognostic marker in CRC patients.