Although tumors tend to be associated with immune cells and inflammation, this immune response often fails to eliminate the cancer and instead promotes cancer progression. Tumor-associated macrophages (TAMs) fail to phagocytose tumor cells, and they also produce signals that suppress the adaptive immune response. We showed that immunosuppressive prostaglandin E₂ (PGE₂) led to the production and activity of the transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) by stimulating the nucleocytoplasmic shuttling of the RNA binding protein Hu antigen R (HuR), which bound to and stabilized CEBPD mRNA in macrophages. An increase in C/EBPδ abundance in macrophages in response to PGE₂ resulted in enhanced production of the immunosuppressive cytokine interleukin-10 (IL-10) and of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells. Furthermore, conditioned medium from C/EBPδ-replete, but not C/EBPδ-deficient, macrophages inhibited the phagocytosis of tumor cells by macrophages, suggesting an autocrine mode of regulation. Immunohistochemical analysis demonstrated that the amount of cytosolic HuR protein correlated with increased C/EBPδ abundance in TAMs in malignant nasopharyngeal carcinoma. Together, these data suggest that the inflammatory PGE₂-HuR-C/EBPδ axis in macrophages promotes tumor progression by preventing the phagocytosis of tumor cells and inducing immunosuppressive cytokine production.