G Protein‐Coupled Receptor Signaling: Implications and Therapeutic Development Advances in Cancers

ABSTRACT G protein‐coupled receptors (GPCRs) are the largest and most diverse class of membrane proteins, mediating cellular responses to a wide range of extracellular stimuli. GPCRs initiate complex intracellular signaling networks that regulate vital physiological functions and are associated with numerous diseases, including various types of cancer. Their conserved seven‐transmembrane (7TM) structure enables these signaling networks by allowing interactions with multiple ligands and intracellular effectors. In several types of tumors, abnormal GPCR signaling promotes carcinogenesis by supporting immune evasion, cell proliferation, and therapeutic resistance. A significant research gap exists in fully understanding the molecular mechanisms behind pathway‐specific activation and biased ligand discovery of GPCRs, which could lead to the development of more effective therapies. This review examines the complexity of GPCRs, with a focus on their role in signaling through the differential activation of pathways regulated by β‐arrestin and G proteins. It discusses how targeted modulation of signaling outcomes by receptor mutants might offer therapeutic benefits in cancer treatment. The review also highlights emerging technologies, such as aptamers, PROTACs, and nanobodies, that more precisely target GPCRs. In addition to exploring receptor structure–function relationships and pathway selectivity, this review provides valuable insights into GPCR‐biased signaling and its implications in cancer biology.