TMEM106A as a Macrophage‐Associated Biomarker of Prognosis in IDH ‐Wildtype Glioma: Integrative Multi‐Omics and Spatial Analyses

Introduction Gliomas remain aggressive despite current therapies, highlighting the urgent need for new biomarkers and targets. Transmembrane protein 106A (TMEM106A), implicated as a tumor suppressor in various cancers, has an unclear role in gliomas. We hypothesized that TMEM106A expression associates with tumor aggressiveness and may serve as a prognostic, microenvironmental biomarker. Methods We integrated TCGA and CGGA bulk RNA‐seq, single‐cell (GSE131928, GSE89567), spatial (Ivy Atlas, Visium), and immunohistochemistry ( n = 79) to evaluate TMEM106A. Differential expression used limma. Survival used Kaplan–Meier and multivariable Cox models. Immune contexture used a 12‐cell‐state deconvolution and CIBERSORT. GSEA assessed hallmark pathways. Drug sensitivity was inferred using pRRophetic. Immunotherapy modeling combined TCGA expression with TCIA immunophenoscore and PD‐L1. Results (1) TMEM106A mRNA is significantly upregulated in high‐grade gliomas compared to lower‐grade gliomas and normal brain. (2) In IDH‐wildtype tumors, differential analyses highlight roles of TMEM106A and TMEM106C; high expression links to poorer prognosis. (3) TMEM106A is an independent prognostic factor associated with aggressive behavior, especially in IDH‐wildtype astrocytomas. (4) Upregulation is confirmed by immunohistochemistry. (5) High TMEM106A associates with pro‐inflammatory signatures and higher inferred fractions of myeloid cells and granulocytes. (6) Single‐cell RNA‐seq shows enrichment in myeloid lineages, and (7) CIBERSORT shows modest positive correlations with polarized macrophage signatures. (8) Spatial transcriptomics shows higher TMEM106A in myeloid‐rich regions, consistent with a microenvironmental readout. (9) In IDH‐wildtype tumors, pRRophetic predicts lower IC50 for multiple targeted agents in TMEM106A‐high tumors. (10) TMEM106A‐high IDH‐wildtype tumors show higher IPS only when PD‐1 is “on,” suggesting a context‐dependent, inflamed‐but‐suppressed state. Conclusion TMEM106A independently predicts survival and correlates with myeloid‐enriched transcriptional states in gliomas. Given its high expression in myeloid lineages in single‐cell data, bulk upregulation is potentially driven by myeloid infiltration rather than tumor‐cell intrinsic mechanisms. All findings are correlative; prospective studies are needed before any clinical use is considered.