In the present study, we explored the specific role of Smad4 in S100A4+ cells during colitis-associated carcinogenesis using S100A4+ cell-specific Smad4 deletion (S100A4Smad4-/-) mice and found that Smad4-specific deletion in S100A4+ cells promoted colitis-associated colon carcinogenesis, suggesting a tumor-inhibiting role of Smad4 signaling in S100A4+ cells. Here, SMAD4 is linked to neoplasm.