Single-cell deconstruction of medulloblastoma microenvironment elucidates subtype-specific immune architectures and prognostic molecular signatures.
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Medulloblastoma (MB), the most common malignant pediatric brain tumor, exhibits molecular heterogeneity classified into WNT, SHH, GP3, and GP4 subtypes, each with distinct prognoses and therapeutic vulnerabilities. Despite advances in multimodal therapies, treatment-related morbidity and incomplete understanding of tumor microenvironment (TME) heterogeneity impede precision medicine. Through integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic profiles from 38 MB specimens, we systematically mapped subtype-specific TME features. WNT MB demonstrated sparse immune infiltration but enriched supportive stromal cells (pericytes, astrocytes/oligodendrocytes) and elevated angiogenesis, correlating with superior prognosis. In contrast, SHH, GP3, and GP4 subtypes exhibited immunosuppressive TMEs dominated by tumor-associated macrophages (TAMs) and T cells. Myeloid subtyping revealed 11 functionally distinct TAM clusters: WNT-enriched microglia-derived M1-polarized subsets with anti-tumor activity, SHH-specific M2-like classical TAMs promoting immune evasion, and GP4-associated ECM-remodeling TAMs driving malignancy. T cell profiling identified CD8+ exhaustion and CD4+ regulatory T cell enrichment in non-WNT subtypes, underpinning immunosuppression. Pseudotime trajectory analysis uncovered myeloid differentiation routes from proliferative TAMs to terminal immunosuppressive subsets, regulated by subtype-specific transcription factors (XBP1, STAT6). CellChat analysis highlighted MIF-CD74 and MDK-LRP1 ligand-receptor pairs as key mediators of tumor-TME crosstalk in non-WNT subtypes. Secretome-receptor clustering stratified MB into three TME-driven subtypes: SHH (matrix remodeling), GP3/GP4 (neuronal differentiation), and WNT (angiogenesis), with tumor cells as primary secretory sources. Prognostic core genes (SHH: EMILIN3, CD163; GP3/GP4: SEMA3A, TULP1) predicted survival outcomes and demonstrated diagnostic specificity. This first comprehensive TME atlas of MB subtypes elucidate mechanisms of immunosuppressive niche formation and provides actionable core targets for precision immunotherapy.