New Insight into the Agonism of Protease-Activated Receptors As an Immunotherapeutic Strategy

The activation and mobilization of immune cells play a crucial role in immunotherapy. Existing therapeutic interventions, such as cytokines administration, aim to enhance immune cell activity. However, these approaches usually result in modest effectiveness and toxic side effects, thereby restricting their clinical application. Protease-activated receptors (PARs), a subfamily of G protein-coupled receptors (GPCRs), actively participate in the immune system by directly activating immune cells. The activation of PARs by proteases or synthetic ligands can modulate immune cell behavior, signalling, and responses to treat immune-related diseases, suggesting the significance of PARs agonism in immunotherapy. However, the agonism of PARs in therapeutical applications remains rarely discussed, since it has been traditionally considered that PARs activation facilitates disease progressions. This review aims to comprehensively summarize the activation, rather than inhibition, of PARs in immune-related physiological responses and diseases. Additionally, we will discuss the emerging immunotherapeutic potential of PARs agonism, providing a new strategic direction for PARs-mediated immunotherapy.