Multi-omics profiling identifies ectopic olfactory receptors as putative drivers of tumor progression and prognostic indicators in clear cell renal cell carcinoma

Olfactory receptors (ORs) are a subclass of G-protein-coupled receptors (GPCRs) that are primarily expressed in olfactory sensory neurons. Furthermore, ORs have recently been identified in the tumor microenvironment (TME) of various cancers, suggesting potential involvement for ORs in tumor progression. However, the roles of ORs in clear cell renal cell carcinoma (ccRCC), the most prevalent and aggressive subtype of kidney cancer, characterized by limited therapeutic response and a 5-year survival rate of only 10% in advanced stages, have yet to be elucidated. In this study, an integrative multi-omics analysis combining bulk transcriptomic profiles from The Cancer Genome Atlas (TCGA) and single-cell RNA- and ATAC-sequencing datasets from ccRCC patients to characterize the context- and cell-type-specific functions of ORs within the TME. Notably, ORs exhibited distinct, cell-type-specific expression profiles within ccRCC TME. OR51E1 was predominantly expressed in pericytes and correlated with vascular remodeling and angiogenic activity, whereas OR2T10 was enriched in malignant epithelial cells and associated with invasive and metastatic potential, with each OR being associated with resistance to therapeutic agents. In addition, OR-based prognostic modeling and tumor clustering both identified unfavorable prognostic signatures associated with poor patient outcomes and TME-related immunosuppression. These findings highlight ectopic OR networks as clinically relevant molecular features of ccRCC progression and position ORs as potential actionable biomarkers and potential therapeutic targets, offering new avenues for precision oncology in ccRCC.