Prostaglandin E2 receptor 4 (EP4) (EP4)

The Prostaglandin E2 receptor 4 (EP4), encoded by the PTGER4 gene, is a high-affinity G protein-coupled receptor (GPCR) that mediates the biological effects of prostaglandin E2 (PGE2) [1, 6, 9]. It is a central component of the PGE2/EP4 signaling axis, which regulates diverse physiological processes including immune modulation, vascular tone, and tissue homeostasis [2, 8]. In oncology, the PGE2/EP4 axis is frequently hijacked by tumors to create an immunosuppressive microenvironment; activation of EP4 on immune cells like dendritic cells and natural killer cells inhibits their anti-tumor activity, while its activation on myeloid-derived suppressor cells (MDSCs) and regulatory T cells promotes immune evasion [1, 7]. Furthermore, EP4 signaling in tumor and endothelial cells drives angiogenesis, lymphangiogenesis, and cancer cell stemness, contributing to metastasis [3, 5]. Therapeutic strategies targeting this axis primarily involve EP4 antagonists, which are being investigated in clinical trials to restore anti-tumor immunity, often in combination with immune checkpoint inhibitors [4, 11]. Additionally, EP4 agonists are explored for their potential in treating ulcerative colitis and promoting bone healing due to the receptor's role in mucosal protection and osteoblast differentiation [2, 4].

Other names

PTGER4Prostanoid EP4 receptorPGE receptor EP4 subtypePGE2 receptor EP4 subtypeProstaglandin E receptor 4

EP4 antagonists block the binding of PGE2 to the EP4 receptor, thereby inhibiting downstream Gs-mediated adenylate cyclase production of cAMP and non-canonical PI3K/Akt and ERK signaling pathways. In oncology, this blockade reverses PGE2-induced immunosuppression in the tumor microenvironment, restores the activity of natural killer and dendritic cells, and reduces the recruitment of myeloid-derived suppressor cells. Conversely, EP4 agonists activate these pathways to promote mucosal healing, bone formation, and vasodilation.