Tissue-colonizing disseminated tumor cells secrete prostaglandin E2 to promote NK cell dysfunction and evade anti-metastatic immunity.

Natural killer (NK) cells are critical for anti-metastatic immunity and can eliminate metastasizing tumor cells within circulation and sites of metastatic seeding. Here, we show that disseminated tumor cells (DTCs) colonizing the mouse lung secrete prostaglandin E2 (PGE₂) to locally induce NK cell dysfunction, allowing outgrowing metastases to escape immune control and establish metastatic disease. Mechanistically, PGE₂ signaling through its receptors EP2 and EP4 mediates NK cell dysfunction, which leads to reprogramming of NK cell gene expression and results in impaired production of anti-metastatic cytokines. In human cancer patients, the PGE₂-EP2/EP4 axis is associated with NK cell dysfunction within distant organ metastases. Disabling EP2/EP4 signaling in NK cells prevents their dysfunction in DTC-colonized lungs and achieves effective NK cell-mediated control of metastatic disease. Our findings reveal a suppressive signaling axis exploited by metastasizing tumor cells to escape immune control in distant organs that could be targeted for metastatic cancer therapy.