Aim: We focused on investigating the role and mechanism of ganodermanontriol (GAN) in regulating the M2 polarization of tumor -associated macrophages in the gastric cancer microenvironment. Methods: M2 polarization of RAW264.7 macrophages was induced by IL -4 or co -culture with MFC, and the expression levels of M1 macrophage markers (TNF-alpha, IFN-gamma, IL-1 beta) and M2 macrophage markers (IL -10, TGF-beta, Arg-1) were detected by enzyme -linked immunosorbed assay (ELISA). The protein expression was assayed by Western -Blotting. For in vitro experiments, a tumor -bearing mouse model was established, with which the CD206 level was detected by histochemistry, and the binding mode between GAN and STAT6 was simulated through molecular dynamics. Results: Both IL -4 and MFC could induce the M2 polarization of macrophages. GAN could inhibit such polarization, which produced unobvious effects on M1 markers, but could suppress the levels of M2 markers. GAN could inhibit the phosphorylated expression of STAT6, and M2 macrophages treated by it had a weakened ability to promote malignant behavior of MFC. According to the results of in vitro experiments, GAN could inhibit tumor growth, suppress the tissue infiltration of CD206 cells, and inhibit the phosphorylated expression of STAT6. Conclusion: Our results show that GAN can inhibit the M2 macrophage polarization in gastric cancer microenvironment, whose mechanism of action is associated with the regulation of STAT6 phosphorylation.