PGE(2) is the key factor needed for MDSCs development, accumulation and functional stability. PGE(2) initiates an EP2/EP4-mediated positive feedback between COX2 and PGE(2) in monocytic precursors, redirecting dendritic cell differentiation to MDSCs. COX2- or EP2/EP4- blockade abrogates MDSC functions and their CXCR4-CXCL12-mediated attraction to cancer environment, providing convenient immunotherapeutic targets.