Background <p>Glioblastoma is one of the most aggressive and lethal forms of brain cancer, characterized by rapid angiogenesis and infiltration of tumor-associated macrophages in the tumor microenvironment (TME). Given the limited efficacy of single-targeting tumor cell therapies against glioblastoma, regulating the TME has emerged as a promising strategy to improve therapeutic outcomes.</p> Materials and methods <p>The Cancer Genome Atlas (TCGA) was used to assess the association between ligand-dependent nuclear receptor corepressor (LCoR) expression and glioblastoma. LCoR expression in patient glioma specimens was examined by qRT‑PCR and Western blot. LCoR was knocked down or overexpressed in glioblastoma cell lines (SF295, SNB19) using lentiviral vectors, followed by functional assays for proliferation, migration, invasion, angiogenesis, chemokine secretion, and monocyte migration. Subcutaneous and orthotopic mouse models were established to evaluate tumor growth, angiogenesis, and macrophage infiltration via immunohistochemistry and immunofluorescence. Transcriptome sequencing was performed on LCoR‑overexpressing cells to explore underlying mechanisms. In addition, mice were treated with the small-molecule compound deoxynyboquinone to assess its therapeutic effect via LCoR‑mediated regulation.</p> Results <p>TCGA analysis reveals lower LCoR expression in glioblastoma than in normal tissues, correlating with improved patient survival. Clinical samples further confirm reduced LCoR expression in tumor versus peri-tumor tissues. LCoR knockdown significantly enhanced the proliferation, migration, and invasion of glioblastoma cells, whereas LCoR overexpression inhibited these malignant phenotypes. Mechanistically, LCoR suppressed VEGF and HIF-1α expression in tumor cells, thereby reducing angiogenesis and tumor sphere formation. Transcriptome sequencing revealed that LCoR is involved in immune regulation. Further experiments demonstrated that LCoR inhibited chemokine secretion, thereby reducing monocyte migration and macrophage M2 polarization. In subcutaneous and orthotopic glioblastoma mouse models, LCoR overexpression suppressed tumor growth by inhibiting angiogenesis and macrophage M2 polarization. Treatment with the deoxynyboquinone reduced angiogenesis and macrophage infiltration in the TME through LCoR-mediated downregulation of MCP-1, thereby blocking glioblastoma progression.</p> Conclusion <p>LCoR serves as a potential therapeutic target against glioblastoma. Upregulating LCoR can inhibit glioblastoma development by suppressing angiogenesis and immune evasion within the TME.</p>