High infiltration of M2-polarized macrophages in the primary tumor indicates unfavorable prognosis and poor overall survival in the patients with triple-negative breast cancer(TNBC).Thus,reversing M2-polarized tumor-associated macrophages in the tumors has been considered as a potential therapeutic strategy for TNBC.Sphingomyelin synthase 2(SMS2)is the key enzyme for sphingomyelin production,which plays an important role in plasma membrane integrity and function.In this study we investigated whether SMS2 inhibitor or SMS2 gene knockout could reduce macrophages M2 polarization and tumor progression in a mouse model of TNBC.We showed that SMS2 mRNA expression was linked to immunosuppressive tumor microenvironment and poor prognosis in TNBC patients.The knockout of SMS2 or application of 15w(a specific SMS2 inhibitor)markedly decreased the generation of M2-type macrophages in vitro,and reduced the tumor weight and lung metastatic niche formation in a 4T1-TNBC mouse model.We further demonstrated that the in vivo antitumor efficacy of 15w was accompanied by a multifaceted remodeling of tumor immune environment reflecting not only the suppression of M2-type macrophages but also diminished levels of regulatory T cells and myeloid-derived suppressor cells leading to a dramatically improved infiltration of antitumor CD8+T lymphocytes.Collectively,our results reveal a novel and important role of SMS2 in the protumorigenic function and may offer a new strategy for macrophage-targeted anticancer therapy.