A timeless chronicle: Effects of cigarette smoke on GPR15 receptor and its oncogenic potential

G-protein-coupled receptors (GPCRs) represent the largest family of membrane receptors encoded in the human genome, with diverse physiological and pathological functions. GPR15, a recently characterized member of this family, has emerged as a receptor of interest due to its significant upregulation and hypomethylation in response to cigarette smoking, a modifiable environmental risk factor implicated in numerous diseases. Initially, it was identified as a coreceptor for viruses, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). It was later deorphanized with the discovery of its endogenous ligand, C10orf99. This review explores the effect of cigarette smoke on GPR15 expression, its different ligands, and the GPR15 signaling axis in various smoking-related cancers, such as lung, gastric, pancreatic, bladder, and colorectal cancers.