Background: Gliomas exhibit substantial intratumoral heterogeneity, which limits prognostic precision and therapeutic efficacy. Selenoproteins are key regulators of redox homeostasis, but their role in glioma progression remains insufficiently defined. This study aimed to characterize glioma cells with high selenoprotein activity and to determine their biological and clinical significance. Methods: We performed integrated multi-omic analyses combining bulk transcriptomic, single-cell transcriptomic, and spatial transcriptomic data to identify and characterize glioma cell states associated with elevated selenoprotein expression. Functional validation was conducted using SELENOS knockdown assays to evaluate effects on glioma proliferation, invasion, tumor growth, macrophage recruitment, CSF1 expression, and macrophage polarization. Results: We identified a malignant glioma cell state, termed SehighMali, characterized by elevated selenoprotein expression and distinct metabolic and immunological features. SehighMali cells showed enhanced oxidative phosphorylation, MYC-associated transcription, and DNA repair activity, and preferentially engaged in immunosuppressive crosstalk with myeloid cells through the CSF1–CSF1R axis. Spatial analyses demonstrated enrichment of SehighMali cells in tumor cores and close colocalization with immunosuppressive myeloid populations. Across bulk cohorts, higher SehighMali abundance was associated with aggressive molecular features, poor clinical outcomes, and a predicted temozolomide-resistant phenotype. SELENOS knockdown suppressed glioma proliferation, invasion, and tumor growth, reduced macrophage recruitment, decreased CSF1 expression, and promoted macrophage polarization toward a pro-inflammatory phenotype. Conclusions: These findings define a selenoprotein-driven malignant glioma state associated with immune evasion and therapeutic vulnerability. They further identify SELENOS as a potential therapeutic target and provide insight into how selenoprotein-related programs contribute to glioma progression.