Integrated multi-omics analyses decipher molecular subtype-associated tumor microenvironment patterns in glioma

Glioma progression is driven by both tumor-intrinsic genetics and tumor microenvironment (TME) heterogeneity. Although tumor-intrinsic heterogeneity has been widely explored, the understanding of the isocitrate dehydrogenase (IDH)-associated TME in glioma remains less clear. In this study, therefore, we integrated bulk and single-cell transcriptomics, spatial transcriptomics, and proteomic data from glioma tissues and patient blood samples to characterize TME composition, subtype-associated molecular patterns, and their prognostic relevance. The data showed that IDH-wildtype (IDH-WT) glioma exhibited complicated TME, enriched in pericytes and immune cells, whereas IDH-mutant (IDH-MU) glioma displayed a TME dominated by oligodendrocytes and neurons. From a TME-related geneset, we identified four subtype-associated gene patterns: 179 genes in IDH-WT (WT-179) associated with extracellular matrix remodeling and angiogenesis; 68 genes in IDH-MU (MU-68) linked to neuronal and synaptic pathways; 30 genes in IDH-MU with chromosome 1p/19q-non-codeletion (M-N-30) enriched in RNA/protein binding; and 83 genes in IDH-MU with chromosome 1p/19q-codeletion (M-C-83) involved in neurodevelopmental processes. Single-cell transcriptomics profiled contributions of pericyte, myeloid, and lymphocyte subpopulations to these patterns, revealing distinct developmental trajectories and functional programs across glioma subtypes. Glioma tissue and serum proteomics detected WT-179-associated proteins and identified POSTN, LTF, PLA2G2A, and ANXA1 as candidate protein markers associated with the IDH-WT TME program. Taken together, this study provided novel insights into the cellular and molecular features of the TME across glioma molecular subtypes and implied TME as a promising therapeutic target for developing novel treatment strategies.