Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis

Glioblastoma multiforme (GBM) is characterized by rapid progression, therapeutic resistance, and a profoundly immunosuppressive tumor microenvironment. Emerging evidence suggests that endoplasmic reticulum (ER)-associated macromolecules play critical roles in tumor adaptation. In this study, we performed a multi-omics investigation of orosomucoid-like protein 2 (ORMDL2), a conserved ER membrane protein involved in sphingolipid biosynthesis and ER stress regulation, and uncovered its regulatory functions in GBM progression. Transcriptomic analyses across The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) revealed elevated ORMDL2 expression in GBM tissues which causes poor prognosis. The MetaCore pathway and Gene Set Enrichment Analysis (GSEA) identified ORMDL2's involvement in antigen presentation via a major histocompatibility complex I (MHC class I), unfolded protein response (UPR), and mitochondrial apoptotic signaling. Single-cell RNA-sequencing data and the Human Protein Atlas showed ORMDL2 enrichment in tumor stromal cells. Pharmacogenomic correlation via the Genomics in Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) database suggested that ORMDL2 expression was associated with resistance to DNA damage response inhibitors such as etoposide, doxorubicin, talazoparib, and might interact with sphingolipid-targeting compounds. Collectively, our findings establish ORMDL2 as a multi-functional macromolecular regulator of immune suppression and therapeutic resistance in GBM, providing new mechanistic insights and potential targets for translational medicines.