Decoding GPCR signaling reprogramming in cancer: molecular mechanisms and therapeutic implications

G protein-coupled receptors (GPCRs) constitute the largest membrane receptor family in the human genome and serve as key regulators of cell signaling, homeostasis, and pharmacologic response. Beyond their classical role in mediating extracellular stimuli through G-protein-dependent and independent pathways, which have a pivotal role of GPCR-mediated signaling pathways, including the cAMP-PKA/EPAC, IP3/PLC, PI3K/Akt/mTOR, and ERK/MAPK cascades, in driving oncogenic proliferation, apoptosis resistance, and metastasis. Furthermore, GPCRs are implicated in tumorigenesis through diverse molecular mechanisms, in which GPCR dysregulation contributes to cancer initiation and progression via aberrations at multiple genomic and regulatory levels, including copy number variations (CNVs), epigenetic modifications, post-transcriptional, and post-translational modifications. Despite their extensive biological roles and druggability, targeting GPCRs in cancer therapy has yielded promising outcomes, notably via SMO and chemokine receptor inhibitors. Overall, we aim to bridge the gap between fundamental GPCR signaling biology and clinical oncology. We integrated the deregulated expression and pathways of GPCR oncogenic processes, with the potential to be actionable biomarkers for tumor screening and clinical practices using GPCR drugable targets. Therefore, we represent and highlight pathway-specific signaling pathways with their tumor microenvironment interactions, drug combination strategies, and molecular imaging and theranostics applied in clinical practice and precision medicine.