Gastric cancer is the third leading cause of cancer deaths around the world. Tumor immunotherapy for unresectable GC is now widely recognized in clinical applications. Given the ineffective immunotherapy and drug resistance, working out the regulatory mechanism of PD-L1 is still necessary. Super enhancers bring about transcriptional dysregulation and contribute to oncogenesis, invasion, and formation of the immunosuppressive microenvironment. RNA binding proteins, zinc-finger protein 36 (ZFP36L1) genes family are able to provoke mRNA degradation. In this study, we inspect the super-enhancer heterogeneity between two subtypes of gastric cancer with differential growth patterns, and establish the immune escape signatures in infiltrative gastric cancer. We elucidate that ZFP36L1 driven by super enhancer promotes IFN-γ-induced PD-L1 expression, and SPI1 is identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate-uridylate rich element in 3′UTR of HDAC3 mRNA, aggravates its mRNA decay, and thereby stimulates PD-L1 abnormal transcriptional activation. Our work reveals the SPI1/ZFP36L1/HDAC3/PD-L1 signaling axis, and enriches the understanding of immune checkpoint therapy in gastric cancer.