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Simple Summary: The mesenchymal (MES) phenotype of glioblastoma (GBM) confers resistance to various therapeutic strategies and results from both tumor-intrinsic genetic alterations and tumor-extrinsic microenvironmental factors. In this study, we sought to identify and validate the key genes that regulate the MES phenotype of glioma via both mechanisms. By integrating bulk tumor data (using the TCGA and CGGA databases) and single-cell sequencing data of GBM, we revealed that the plasminogen activator, urokinase receptor (PLAUR) is the hub gene of the protumor microenvironment, encompassing hypoxia and immunosuppression, and we elucidated its role in driving the MES transition through both tumor-intrinsic function and cell-to-cell interaction. Our findings indicate that PLAUR may be a potential target for GBM treatment, as our research elucidated its functions through a comprehensive study. The mesenchymal (MES) phenotype of glioblastoma (GBM) is the most aggressive and therapy-resistant subtype of GBM. The MES phenotype transition during tumor progression results from both tumor-intrinsic genetic alterations and tumor-extrinsic microenvironmental factors. In this study, we sought to identify genes that can modulate the MES phenotype via both mechanisms. By integrating weighted gene co-expression network analysis (WGCNA) and the differential expression analysis of hypoxia-immunosuppression-related genes, we identified the plasminogen activator, urokinase receptor (PLAUR) as the hub gene. Functional enrichment analysis and GSVA analysis demonstrated that PLAUR was associated with the MES phenotype of glioma and the hypoxia-immunosuppression-related microenvironmental components. Single-cell sequencing analysis revealed that PLAUR mediated the ligand–receptor interaction between tumor-associated macrophages (TAMs) and glioma cells. Functional experiments in vitro with cell lines or primary glioma cells and xenograft models using BALB/c nude mice confirmed the role of PLAUR in promoting the MES phenotype of GBM. Our findings indicate that PLAUR regulates both glioma cells and tumor cell-extrinsic factors that favor the MES phenotype and suggest that PLAUR might be a potential target for GBM therapy. [ABSTRACT FROM AUTHOR]