Pancreatic cancer is a highly malignant disease with poor prognosis. Accumulating evidences indicate that prostaglandin E2 (PGE2) can promote cancer progressionreprogramming tumor microenvironment (TME). On one hand, PGE2 can regulate immune cells, tumor cells, cancer-associated fibroblasts and endothelial cells inTME to boost growth,invasion and metastasis of pancreatic cancer. On the otherhand,exosomes tumor cells influence the synthesis, release and uptake of PGE2 and enhance its reprogramming abilities. Furthermore, PGE2 even plays an important role in the development of therapy resistancestimulating tumor repopulation and inducing epithelial-mesenchymal transition. Hence, PGE2 might be a potential therapeutic target for intervention of pancreatic cancer.