Prostaglandin E2 receptor 4 (EP4)

Class

EP4 receptor antagonist (small molecule)

Pathway

PGE2/EP4 immunosuppressive signaling in the tumor microenvironment

Prostaglandin E2 receptor 4 (EP4) is a G-protein-coupled receptor for prostaglandin E2 (PGE2), a lipid signaling molecule produced abundantly by many tumors through the cyclooxygenase (COX) pathway. Within the tumor microenvironment, PGE2 acting through EP4 on immune cells dampens antitumor immunity: it restrains T-cell activation, favors the expansion of regulatory and myeloid suppressor cell populations, and skews macrophages toward a tumor-tolerant phenotype. Because this creates a local immunosuppressive shield around cancer cells, blocking EP4 with a small-molecule antagonist is a strategy intended to loosen that shield and allow the immune system, particularly cytotoxic T cells, to recognize and attack tumor tissue more effectively. This mechanism is of broad interest in oncology, especially in tumors with high COX-2/PGE2 output, and is often considered in combination with other immune-activating therapies such as checkpoint inhibitors, since the two approaches act on complementary aspects of immune evasion. Beyond oncology, PGE2-EP4 signaling also participates in inflammatory and vascular processes, meaning the receptor's biology extends well past cancer, but its role in suppressing antitumor immunity is the primary rationale for developing selective antagonists in this therapeutic context.