BACKGROUND: Glioma is a disease typically characterized by immunosuppression, which explains its poor prognosis. Therefore, it is urgent to elucidate new molecular mechanisms of immune-supervised escape to improve the efficacy of immunotherapy. Recent studies have identified secreted phosphoprotein 1(SPP1) as a pro-inflammatory and chemokine in macrophages that mediates crosstalk between the innate immune system and tumor cells. We aimed to detect the role of SPP1 in immunomodulation in glioma. METHODS: We enrolled 916 patients from different ethnic groups, including 603 patients from The Cancer Genome Atlas (TCGA) database and 313 patients from the Chinese Glioma Genome Atlas (CGGA) database. We performed enrichment analysis and used GSVA to calculate the immune pathway and immune cell infiltration scores of SPP1.In addition, we investigated the correlation between SPP1 and immune checkpoint genes as well as inflammation-related genes. RESULTS: The expression of SPP1 is significantly elevated in IDH wild-type gliomas and high-grade gliomas, particularly in the mesenchymal subtype, and it serves as an independent prognostic factor for overall survival (OS) in glioma patients. SPP1 influences macrophage activation, cytokine secretion, and polarization and exhibits a strong association with various lymphocytes, including T, B and NK cells. Furthermore, SPP1 is strongly correlated not only with immune checkpoint genes but also with various inflammation-related genes. CONCLUSION: In conclusion, SPP1 expression is tightly linked to the molecular pathology of gliomas and is highly correlated with immune checkpoints. It contributes to glioma immune evasion, positioning SPP1 as a promising new target for immunotherapy in glioma.