In this work, we demonstrated that PGE2-EP2/EP4 signaling promoted active inflammation through NF-κB-mediated upregulation of target proinflammatory and angiogenesis genes in myeloid cells and simultaneously induced immunosuppression through mregDC-mediated Ccl22 and Ccl17 production to facilitate Treg recruitment and activation in the tumor. We found that EP2/EP4 inhibition reduced NF-κB dependent gene expression, decreased Tregs infiltration and activation, and suppressed LLC1 tumor growth in mouse model. Moreover, we analyzed TCGA database and found that expression of PTGER2 and PTGER4 (encoding EP2 and EP4) together correlated with poor prognosis in several cancers. Thus, PGE₂ -EP2/EP4 signaling induces immunosuppression in proinflammatory tumor microenvironment, which is amenable to EP2 and EP4 inhibitor.