Macrophage-specific Smad7 restrains colorectal cancer progression by suppressing STAT6-mediated M2 polarization

Macrophages play a crucial role in the tumor microenvironment, and their polarization states significantly impact the progression of colorectal cancer (CRC). In this study, we explored the macrophage-intrinsic function of Smad7 using patient datasets, tissue-based analyses, conditional knockout mouse models, and macrophage cell systems. Smad7 expression was reduced in clinically aggressive CRC and was preferentially decreased within CD206-positive macrophage-associated regions, where it inversely correlated with CD206 expression, whereas no comparable reduction was observed in E-cadherin-positive epithelial regions. The macrophage-specific deletion of Smad7 led to a marked increase in CRC incidence, accompanied by a shift toward an M2-like phenotype. Smad7-deficient macrophages exhibited heightened expression of M2 markers and decreased levels of M1-associated genes, which correlated with increased phosphorylation of STAT6 following IL-4/IL-13 stimulation. In contrast, overexpression of Smad7 inhibited M2 polarization and enhanced the expression of M1 markers. Mechanistically, Smad7 positively influenced the transcription of protein tyrosine phosphatase non-receptor type 2 (PTPN2), a negative regulator of STAT signaling, by functioning as a coactivator of IRF1 at the PTPN2 promoter. The loss of Smad7 resulted in reduced PTPN2 expression, leading to sustained STAT6 activation and promoting M2 polarization. Notably, knocking down PTPN2 mirrored the expression patterns of M2 markers observed with Smad7 deficiency, and the absence of PTPN2 in Smad7-overexpressing cells negated the suppression of STAT6 signaling and M2 marker expression. Overall, these findings reveal a previously unrecognized role for Smad7 in macrophages as a transcriptional regulator of PTPN2, which restricts STAT6-mediated M2 polarization and limits colorectal tumorigenesis. Targeting the Smad7–PTPN2–STAT6 axis may offer new therapeutic avenues for reprogramming macrophage function in CRC.