The PGE₂–NK-cell Axis in Tumor Immune Escape: Mechanisms and Therapeutic Targeting

Natural killer (NK) cells sit at the center of tumor immune surveillance. Their contribution goes beyond direct killing—they produce cytokines, release chemokines, and help recruit dendritic cells. Yet solid tumors often contain high local levels of prostaglandin E2 (PGE₂) , generated by cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) , and this PGE₂-rich environment dampens NK-cell responses at several points. This review examines how tumor-derived PGE₂ signals through EP2/EP4 (E-prostanoid receptors 2 and 4) and the downstream cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A) cascade. The consequences include altered NK-cell activation, cytokine output, receptor expression, immune-synapse organization, cytotoxicity, migration, and antimetastatic activity. We also compare ways to interrupt this axis: pharmacological inhibitors of PGE₂ synthesis, selective or dual EP2/EP4 blockade, and cell-intrinsic engineering approaches aimed at making NK cells less sensitive to PGE₂. Attention is paid to inconsistencies among experimental models and to whether interventions restore NK-cell function directly or act more broadly on the tumor. Biomarkers that might support patient selection are discussed as well. Current evidence suggests the PGE₂–NK-cell axis is a druggable immunosuppressive circuit, although clinical translation will likely require pathway-based stratification and prospective pharmacodynamic assessment.