TGFB2 as a Prognostic Biomarker Associated with Myeloid-Enriched, Multi-Checkpoint-Activated Immunosuppression in Diffuse Glioma: A Multi-Cohort Transcriptomic Study

Background/Objectives: TGFB2 is the dominant TGF-β isoform in glioma, and isolated experimental studies have implicated it in immunosuppressive signaling; however, its prognostic value and systematic association with the tumor immune microenvironment across the diffuse glioma spectrum have not been comprehensively characterized in large clinical cohorts. Methods: A multi-cohort transcriptomic study was conducted using TCGA (n = 667) as discovery and CGGA (n = 404) as validation, integrating survival analysis, functional enrichment, immune deconvolution by ssGSEA and MCP-counter, immune checkpoint correlation, and TISCH2-based single-cell localization. Results: TGFB2 was consistently overexpressed in glioma relative to normal brain at both mRNA and protein levels, with expression highest in GBM (median 10.60 vs. 8.45 in LGG; p < 2.2 × 10−16) and increasing across WHO grade. High TGFB2 predicted worse overall survival in both cohorts (TCGA: 648 vs. 2907 days; CGGA: 863 vs. 3107 days; both p < 0.0001), with 3-year AUCs of 0.823 and 0.714, and retained independent prognostic significance in the CGGA multivariate model (HR = 1.343; p = 3.2 × 10−4). Hallmark GSEA identified consistent enrichment of interferon signaling, epithelial–mesenchymal transition, TNFα/NF-κB, and IL-6/JAK/STAT3 pathways. ssGSEA and MCP-counter concordantly demonstrated significantly expanded myeloid, monocytic, and stromal populations across both cohorts. TGFB2 correlated positively with PD-L1, TIM-3, ICOS (ρ = 0.449), IL2RA (ρ = 0.397), CTLA4 (ρ = 0.375), and TIGIT (ρ = 0.170) in TCGA, with all associations replicated in CGGA. Conclusions: TGFB2 is an adverse prognostic biomarker in diffuse glioma coupled to a myeloid-enriched, multi-checkpoint-activated tumor microenvironment, supporting its evaluation as a stratification biomarker in TGF-β/checkpoint combination immunotherapy trials.