Prostaglandin E2 receptor 2 and Prostaglandin E2 receptor 4 (EP2/EP4)

The EP2 and EP4 receptors are G protein-coupled receptors (GPCRs) that serve as primary mediators for Prostaglandin E2 (PGE2), a lipid signaling molecule central to inflammation and cancer progression. These receptors are prominently expressed on immune cells, such as T cells and macrophages, as well as stromal cells like fibroblasts and endothelial cells within the tumor microenvironment. Activation of EP2 and EP4 typically triggers the Gs-cAMP-PKA signaling pathway, which in oncogenic contexts promotes an immunosuppressive environment by inhibiting cytotoxic T cell and natural killer cell activity while recruiting regulatory T cells and myeloid-derived suppressor cells. Beyond immune evasion, the PGE2-EP2/EP4 axis drives tumor cell proliferation, invasion, and the production of angiogenic factors like VEGF. Therapeutic targeting of these receptors, particularly through dual antagonism, aims to reverse this immunosuppression and enhance the efficacy of other immunotherapies like checkpoint inhibitors. Clinical development of dual EP2/EP4 antagonists is currently focused on treating various solid tumors where the COX-2/PGE2 pathway is overactive.

Other names

PTGER2PTGER4Prostanoid EP2 receptorProstanoid EP4 receptorPGE2 receptor 2PGE2 receptor 4

Antagonism of the EP2 and EP4 receptors to block PGE2-mediated signaling, thereby reversing immunosuppression in the tumor microenvironment and inhibiting tumor growth, metastasis, and angiogenesis.