Lactic acid-induced M2-like macrophages facilitate tumor cell migration and invasion via the GPNMB/CD44 axis in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral and maxillofacial malignancies, characterized by a low five-year survival rate primarily caused by invasion and metastasis. The progression of OSCC is influenced by macrophage-mediated immunosuppression, which contributes to both local invasion and distant metastasis. Herein, it is of great necessity to explore the molecular mechanisms underlying the crosstalk between OSCC cells and macrophages, as it remains unclear. In the present study, we found that lactic acid orchestrated intracellular communication in the tumor microenvironment. Glycoprotein non-metastatic protein B (GPNMB), a remarkable molecule preferentially expressed by tumor-associated macrophages (TAMs), was significantly highly expressed in the OSCC tissue. The results showed that lactic acid induced macrophage polarization towards an M2-like phenotype and orchestrated GPNMB secretion from macrophages. Furthermore, paracrine GPNMB played a critical role in triggering tumor-promoting activities such as facilitating tumor cell migration, invasion, and epithelial–mesenchymal transition (EMT). In terms of molecular mechanism, GPNMB functionally interacted with the CD44 receptor, and then partially activated the PI3K/AKT/mTOR signaling cascade. Silencing of CD44 could attenuate the tumor-promoting effects of GPNMB in OSCC cells. Collectively, our findings decipher a positive feedback loop in which tumor cells metabolically interact with macrophages in the OSCC microenvironment, highlighting the potential for therapeutic targeting of the GPNMB/CD44 axis as a promising strategy for treating OSCC.