Comprehensive Transcriptomic Analysis Reveals Cell-Type-Specific Roles of Human Odorant Receptors in Glioblastoma and the Tumor Microenvironment

Odorant receptors (ORs), which constitute approximately 50% of all human G protein-coupled receptors, are increasingly recognized for their diverse roles beyond odor perception, including functions in various pathological conditions like brain diseases and cancers. However, the roles of ORs in glioblastoma (GBM), the most aggressive primary brain tumor with a median survival of only 15 months, remain largely unexplored. Here, we performed an integrated transcriptomic analysis combining The Cancer Genome Atlas RNA-seq and single-cell RNA sequencing data from GBM patients to uncover cell-type-specific roles of ORs within the tumor and its microenvironment. Our findings reveal that ORs display distinct expression patterns, with <i>OR51E1</i> enriched in pericytes linked to vascular remodeling and angiogenesis, OR2B11 associated with tumor-associated macrophages supporting immunosuppressive phenotypes, and OR2L13 correlated with synaptic activity in recurrent tumors, potentially mediating treatment-induced neuronal adaptations. These results highlight ORs as potential therapeutic targets, offering new insights into their regulatory roles in GBM progression, immune modulation, and treatment resistance.