The Myeloid Biomarker MS4A6A Drives an Immunosuppressive Microenvironment in Glioblastoma via Activation of the PGE2 Signaling Axis

Glioblastoma (GBM) remains one of the most lethal brain tumors, characterized by extensive immune evasion and a macrophage-dominated tumor microenvironment (TME). However, the molecular determinants governing tumor-associated macrophage (TAM) states and their immunoregulatory functions remain poorly understood. We integrated bulk- and single-cell transcriptomic datasets (TCGA, CGGA, Ivy GAP, and Brain Immune Atlas) to systematically characterize the expression, prognostic relevance, and immune contexture of the myeloid biomarker membrane-spanning 4-domain A6A, <i>MS4A6A</i>, in GBM. Differential expression, survival, and pathway enrichment analyses were performed. Single-cell mapping and CellChat modeling delineated <i>MS4A6A</i>-associated TAM subpopulations, intercellular communication networks, and ligand-receptor signaling dynamics. Spatial transcriptomic validation and pharmacogenomic modeling were conducted to assess anatomic enrichment and therapeutic vulnerabilities. High <i>MS4A6A</i> expression predicted unfavorable survival and correlated with increased stromal and immune infiltration. Single-cell analyses localized <i>MS4A6A</i> predominantly to TAMs, especially Regulatory- and Ribo-TAM states enriched for antigen presentation, T-cell regulation, and ribosomal biogenesis pathways. CellChat analysis revealed that <i>MS4A6A</i>-high TAMs exhibited markedly enhanced communication with CD4⁺ T cells and Tregs through upregulated PGE₂-PTGER2/PTGER4, PECAM1-CD38, and THBS1-CD36 signaling axes, implicating <i>MS4A6A</i> in prostaglandin-driven immune suppression. Spatial profiling confirmed preferential localization of <i>MS4A6A</i> within perivascular and angiogenic niches. Pharmacogenomic prediction indicated that <i>MS4A6A</i>-high tumors were more sensitive to ERK, mTOR, and CDK4/6 inhibition. <i>MS4A6A</i> defines a macrophage-centered, immunosuppressive ecosystem in GBM, mediated by the activation of the PGE₂ signaling axis. These findings position <i>MS4A6A</i> both as a prognostic biomarker and as a potential therapeutic node linking myeloid reprogramming to actionable pathway vulnerabilities in glioblastoma.