G protein-coupled receptors (GPCRs), the largest family of currently approved drug targets, are rarely targeted for cancer therapy. There is limited research on the role of GPCRs in pan-cancer, particularly regarding the underlying causes of their abnormal expression. The abnormal expression of GPCRs in tumors has generally been attributed to mutations and promoter methylation. However, transcriptional regulatory elements of GPCRs, such as G-quadruplexes (G4s), superenhancers (SEs), and mRNA structure, remain poorly understood. Then, these regulatory elements were explored by utilizing PRECOG, ROSE, and ViennaRNA algorithms. Meanwhile, cancer prognosis-related GPCRs were found based on different expression analyses and Cox regression. A total of 326 differentially expressed GPCRs were then identified, with 3,151 significant HR (hazard ratios) records in pan-cancer. Notably, most cancer prognosis-related GPCRs are coupled with Gi (GNAI1, GNAI2, and GNAI3) and Gq/11 signaling pathways. Moreover, G4s, SEs, and mRNA structure could be utilized to explain some of the abnormal expression for cancer prognosis-related GPCRs. Additionally, some of these GPCRs have known drug targets such as GCGR, CXCR4, GPR55, and so on. For an example of drug repurposing, four drugs (i.e., theophyline, caffeine, enprofylline, and flavone) were found that could be combined with immunotherapy for PAAD therapy patients. Finally, we developed GPCR-PCA (G protein-coupled receptors in pan-cancer), a web-based tool that provides fast, customizable queries based on our GPCR-related cancer analysis to facilitate clinical research targeting GPCRs. GPCR-PCA is available at http://gpcrpca.lsbz.store/.
