Dazap1 Promotes Oral Squamous Cell Carcinoma Progression Via Spp1+ Macrophages

To elucidate the mechanism by which DAZAP1-mediated aberrant energy metabolism in tumor cells regulates the differentiation of SPP1+ macrophages and promotes the progression of oral squamous carcinoma. We established DAZAP1-knockdown/overexpressing OSCC cell models and identified its regulation of glycolysis through RNA-seq and GSEA analysis, validated by Seahorse and WB assays. STRING-based PPI network and RT-qPCR/ELISA confirmed DAZAP1′s targeting of LDHA expression and lactate secretion. Single-nucleus RNA-seq and IHC revealed enriched SPP1+ macrophages in DAZAP1-high tumors, with co-culture experiments demonstrating DAZAP1-mediated lactate-induced macrophage polarization. Functional assays (siRNA knockdown, Transwell) verified SPP1+ macrophages' role in promoting OSCC invasion/migration, while clinical tissue analysis showed their significant correlation with poor patient prognosis. DAZAP1 promotes oral squamous cell carcinoma progression by enhancing glycolytic reprogramming and lactate secretion, which drives SPP1+ macrophage differentiation and functional polarization. These tumor-educated SPP1+ macrophages secrete OPN to facilitate cancer invasion. Clinical validation confirms that SPP1+ macrophage infiltration correlates with disease progression and poor prognosis. DAZAP1 promotes OSCC progression by upregulating glycolysis to induce SPP1+ macrophage differentiation in the tumor microenvironment.