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.