Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target

Tumor metastasis remains the most lethal and elusive aspect of cancer progression, accounting for the vast majority of cancer-related deaths despite significant advances in treatment. Although our understanding of the molecular mechanisms underlying metastasis has improved over the past decades, effective therapeutic interventions remain limited. Protease-activated receptor-2 (PAR-2) is one of only four G protein-coupled receptors (GPCR) that are uniquely activated by a proteolytic cleavage event that generates a tethered ligand derived from the receptor itself, in contrast to other GPCRs which are activated by soluble ligands present in the extracellular environment. PAR-2, and many of the pro-inflammatory serine proteases that activate it, are overexpressed in advanced-stage cancers. Emerging evidence implicates PAR-2 signaling in multiple cellular processes that drive metastatic progression. Pharmacological inhibitors of PAR-2, initially developed to treat chronic pain and inflammatory conditions, may be repurposed to exploit metastatic vulnerabilities in tumors while sparing normal physiological functions. This review examines the molecular mechanisms by which PAR-2 signaling promotes metastasis and explores the potential of PAR-2-targeted antagonists-alone or in combination with existing cancer therapies-to improve clinical outcomes in patients with advanced malignancies.