Based on our observations and current literature, we propose that both EP2 and EP4 fosters human M-MDSC transition towards a suppressive pro-tumor state able to dampen T cell and NK cell responses, arguing for the combined usage of EP2 and EP4 antagonists to prevent a tumor-derived PGE2 imprinted phenotype of M-MDSCs. This evidence concerns the gene PTGER4 and neoplasm.