Neutral ceramidase (NcDase) regulates breast cancer progression by metabolic programming of TREM2-associated macrophages. NcDase deficiency in breast cancer models accelerates tumor growth by promoting the metabolic reprogramming of tumor-associated macrophages (TAMs) toward an immune-suppressive state. This reprogramming enhances tumor growth and indirectly induces the exhaustion of CD8+ T cells. Mechanistically, NcDase is required for the generation of lipid droplets and lipolysis, which generate fatty acids for fatty acid oxidation (FAO) and orchestrate macrophage metabolism. Ceramide, a metabolite of NcDase, reprograms TAMs toward immune suppressive TREM2+ TAMs, which promote CD8+ T cell exhaustion. TAMs play a critical role in cancer development by promoting angiogenesis and enhancing tumor cell invasion and metastasis. NcDase deficiency leads to increased lipid droplet accumulation and fatty acid oxidation in TAMs, which supports tumor growth. Additionally, NcDase deficiency promotes the expression of TREM2 in TAMs, which is associated with T cell exhaustion in breast cancer. The study highlights the role of NcDase in regulating the metabolic and functional state of TAMs, which in turn influences the immune response and tumor progression. NcDase deficiency enhances the immunosuppressive phenotype of TAMs, which suppresses the cytotoxic capabilities of CD8+ T cells and induces their exhaustion. These findings suggest that NcDase is essential for maintaining anticancer immunity and that its deficiency contributes to tumor progression by promoting the development of immunosuppressive TAMs.Neutral ceramidase (NcDase) regulates breast cancer progression by metabolic programming of TREM2-associated macrophages. NcDase deficiency in breast cancer models accelerates tumor growth by promoting the metabolic reprogramming of tumor-associated macrophages (TAMs) toward an immune-suppressive state. This reprogramming enhances tumor growth and indirectly induces the exhaustion of CD8+ T cells. Mechanistically, NcDase is required for the generation of lipid droplets and lipolysis, which generate fatty acids for fatty acid oxidation (FAO) and orchestrate macrophage metabolism. Ceramide, a metabolite of NcDase, reprograms TAMs toward immune suppressive TREM2+ TAMs, which promote CD8+ T cell exhaustion. TAMs play a critical role in cancer development by promoting angiogenesis and enhancing tumor cell invasion and metastasis. NcDase deficiency leads to increased lipid droplet accumulation and fatty acid oxidation in TAMs, which supports tumor growth. Additionally, NcDase deficiency promotes the expression of TREM2 in TAMs, which is associated with T cell exhaustion in breast cancer. The study highlights the role of NcDase in regulating the metabolic and functional state of TAMs, which in turn influences the immune response and tumor progression. NcDase deficiency enhances the immunosuppressive phenotype of TAMs, which suppresses the cytotoxic capabilities of CD8+ T cells and induces their exhaustion. These findings suggest that NcDase is essential for maintaining anticancer immunity and that its deficiency contributes to tumor progression by promoting the development of immunosuppressive TAMs.