Prostaglandin D2 (PGD2) is a biologically active substance with important roles in a variety of physiological and pathological processes. PGD2 exerts its biological functions mainly through prostaglandin D2 synthase (PGDS), which is closely related to inflammation and immune regulation. Recent studies have found that PGD2 and its synthase, PGDS, are able to directly inhibit tumor cell proliferation, induce apoptosis, suppress migration and invasion, and further regulate the tumor immune microenvironment to affect the immunotherapy of tumors, demonstrating good tumor therapeutic potential. In this paper, we review the biological properties of PGD2 and its synthase, focusing on its role in the immunotherapy of tumor models. We explore the immunotherapeutic efficacy of PGD2 and its synthase, and their roles in promoting immune cell infiltration in the tumor microenvironment, and discuss their potential as new targets for tumor therapy.