Proteomic Profiling of Gliomas Unveils Immune and Metabolism-Driven Subtypes with Implications for Anti-Nucleotide Metabolism Therapy

Abstract

Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made in glioma at the genomic and transcriptomic levels, comprehensive proteomic characterizations and their implications remain largely unexplored. Here, we performed proteogenomic characterization of gliomas using 343 FFPE tumor samples and 53 normal-appearing brain samples from 188 patients, which was integrated with genomic panel data and clinical information. Proteomics profiles uncovered two subgroups: Subgroup 1, termed the “metabolism subgroup” (S-Me), characterized by an enrichment of metabolism-related proteins; and Subgroup 2, named the “immune subgroup” (S-Im), showing an upregulation of immune and inflammatory proteins. These proteomic subgroups exhibited significant differences in prognosis, tumorigenesis, microenvironment dysregulation and potential therapeutics, emphasizing the critical roles of metabolism and immune processes in glioma biology and patient outcomes. By delving into metabolic pathways guided by our proteomic findings, DPYD and TYMP were further identified as potential prognostic biomarkers associated with nucleotide metabolic reprogramming. Functional validation using GSCs and animal models highlighted nucleotide metabolism as a promising therapy against gliomas. The integrated multi-omics analysis introduces a novel proteomic classification for gliomas, and also identified two new metabolic biomarkers, DPYD and TYMP, which offer insights into the molecular pathogenesis and identify treatment opportunities.