Increasing evidence indicates that abnormal circRNA expression contributes significantly to gastric cancer progression; therefore, understanding the underlying biological roles and molecular mechanisms of these dysregulated circRNAs is essential for the discovery of novel therapeutic strategies. To screen for circRNAs associated with metastasis and immunotherapy response in gastric cancer, a circRNA expression profiling analysis was performed on primary tumors, distant metastatic lesions, and tumor samples exhibiting either sensitivity or resistance to anti–PD-1 treatment. Based on this analysis, circDLG1 expression was further examined in an independent and larger collection of gastric cancer specimens. Functional experiments were carried out to determine the contribution of circDLG1 to malignant progression using both cell-based models and animal studies. In addition, the influence of circDLG1 on the therapeutic efficacy of PD-1 blockade was assessed in vivo. The molecular interaction between circDLG1 and miR-141-3p was validated through RNA immunoprecipitation combined with reporter gene assays. CircDLG1 expression was markedly elevated in metastatic gastric cancer lesions and in tumors that failed to respond to PD-1 blockade, and its high expression correlated with aggressive clinicopathological features and poor outcomes in patients receiving anti-PD-1 therapy. Forced overexpression of circDLG1 enhanced gastric cancer cell growth, motility, invasiveness, and immune escape capabilities. At the mechanistic level, circDLG1 directly bound miR-141-3p, functioning as a competing endogenous RNA that relieved miR-141-3p–mediated repression of CXCL12, thereby facilitating tumor progression and diminishing sensitivity to PD-1–targeted immunotherapy. Collectively, these results reveal that circDLG1 enhances malignant behaviors—including cellular growth, motility, invasiveness, and immune escape—in gastric cancer, and highlight a previously unrecognized contribution of circRNAs to the molecular mechanisms driving gastric cancer progression.
