Tartrate-resistant acid phosphatase 5 regulates the metabolic flexibility of macrophages in the tumor microenvironment, thereby influencing their functional fate and modulating tumor growth

Macrophages play a crucial role in anti-tumor immunity, and their dysfunction within the tumor microenvironment contributes to tumor growth and distant metastasis, posing a significant obstacle to cancer immunotherapies. Understanding the molecular checkpoints in macrophages could provide potential therapeutic strategies for cancer treatment. Tartrate-resistant acid phosphatase 5 (ACP5), also known as TRAP5, is an enzyme primarily expressed by osteoclasts and certain immune cells, involved in bone remodeling and immune regulation. Recent research has indicated that ACP5 promotes tumor growth and metastasis in various cancers. However, its specific role within the tumor microenvironment, particularly regarding its effect on macrophages, remains unclear. This study shows that ACP5 is highly expressed in macrophages within breast cancer tissues, as identified through single-cell RNA sequencing. Using ACP5-deficient mice, we observed a significant reduction in tumor burden, metastatic potential, and epithelial-mesenchymal transition in both orthotopic and spontaneous breast cancer models. Mechanistically, ACP5 regulates macrophage polarization, promoting an anti-inflammatory (M2) phenotype that aids tumor progression and metastasis. Notably, ACP5 deletion in bone marrow-derived macrophages impairs AMPK phosphorylation, shifting their metabolism toward glycolysis. This metabolic shift enhances their pro-inflammatory (M1) phenotype, increasing anti-tumor activity against cancer cells. Our findings underscore the vital role of ACP5 in macrophage-mediated immunosuppression and tumor progression, presenting a promising therapeutic target for breast cancer treatment.