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The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self‐renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L‐PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients’ prognosis. Moreover, the expression of L‐PTGDS and PTGDR2 was negatively correlated with the GC‐CSC markers Sall4 and Lgr5 in GC tissues. Second, L‐PTGDS and PTGDR2 expression were knocked down in CSC‐like cells, resulting in enhanced expression of CSC markers and self‐renewal ability. Direct PGD2 stimulation and L‐PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC. S tem  C ells   2018;36:990–1003

PGD2/PTGDR2 Signaling Restricts the Self‐Renewal and Tumorigenesis of Gastric Cancer