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Natural killer (NK) and unconventional γδ T cells, by their ability to sense ligands induced by oncogenic stress on cell surface and to kill tumor cells without a need for clonal expansion, show a great therapeutic interest. They use numerous activating and inhibitory receptors which can function with some independence to trigger or inhibit destruction of target cells. Previous reports demonstrated that PGE2 is able to suppress the destruction of some tumor cell lines by NK and γδ T cells but it remained uncertain if PGE2 interferes with the different activating receptors governing the cytolytic responses of NK and γδ T cells. In this report, using the model of specific redirected lysis of the mouse FcγR+ cell line P815, we clearly demonstrate that the major NK receptors (NKR): NKG2D, CD16 and natural cytotoxicity receptors (NCR: NKp30, NKp44, NKp46) and γδ T cell receptors TCR Vγ9Vδ2, NKG2D and CD16 are all inhibited by PGE2. As is the case with γδ T cells, we show that PGE2 binds on E-prostanoid 2 (EP2) and EP4 receptors on NK cells. Finally, we delineate that the signaling of the blockade by PGE2 is mediated through a cAMP-dependent activation of PKA type I which inhibits early signaling protein of cytotoxic cells. In the discussion, we focused on how these data should impact particular approaches in the treatment of cancer.