GPCR-G protein signalling and its mutational landscape in cancer-Driver or passenger.

G protein-coupled receptors (GPCRs) play a crucial role in cellular signalling, regulating various physiological processes. Abnormal expression and mutations of GPCRs have been implicated in several types of cancer, influencing tumour initiation, progression and immune response. In this review, we present an overview of recent research on GPCR involvement in cancer and discuss the evidence supporting whether mutations in GPCRs act as cancer driver or passenger. Accumulation of GPCR mutations in some highly conserved structural motifs and the mutually exclusiveness observed between G_i-coupled GPCRs and G protein subunit alpha S (GNAS)-activating mutations indicate their potential driving role in cancer. However, the functional redundancy of GPCR signalling networks together with the widespread but low frequency distribution of GPCR mutations indicate that they may rather act as passengers. The future of GPCR drug discovery hinges on overcoming challenges related to data availability and the integration of GPCR research with broader cancer studies using multiomics approaches.