Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy.

Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, cellular context and biased coupling to G-protein αq (Gαq), G-protein α12/13 (Gα12/13) and β-arrestin. PAR-2 is best understood not as a simple inflammatory receptor but as a proteolytic rheostat that converts diverse coagulation, inflammatory, microbial and stromal protease inputs into distinct oncogenic programmes. Colorectal cancer and pancreatic ductal adenocarcinoma provide complementary models: in colorectal cancer, PAR-2 links mucosal inflammation and coagulation to proliferation, metastatic competence and resistance to epidermal growth factor receptor (EGFR)-targeted therapy, whereas in pancreatic cancer, it is embedded in a tissue-factor-rich desmoplastic microenvironment that promotes invasion, immune exclusion and chemoresistance. Therapeutic strategies suggested by this framework include direct and biased PAR-2 modulators, upstream protease and factor Xa (FXa) inhibition, statin repurposing and activated-fragment biomarkers such as the PAR-2 activation neoepitope (PRO-PAR2). These strategies must be applied under biomarker guidance, since PAR-2 blockade may benefit inflammation-dominant tumours yet prove counterproductive where PAR-2 sustains antitumour immunity.