The effectiveness of targeted therapies in prolonging survival for gastric cancer patients remains limited, largely due to off-target effects and tumor immune evasion. Circular RNAs (circRNAs) are abundant in tumor tissues and serve as potential biomarkers and therapeutic targets. The role of hsa_circ_0136666 in promoting gastric cancer cell proliferation was examined using Western blot, qRT-PCR, fluorescence in situ hybridization (FISH), and flow cytometry. Tumor immune evasion was investigated in tumor-bearing mice through tissue immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and flow cytometric analysis. Expression differences of circRNAs in clinical samples were assessed using tissue microarray FISH. The impact of siRNA on enhancing anti-PD-L1 therapy and modulating the tumor immune microenvironment was evaluated in a coadministration model. Hsa_circ_0136666 was highly expressed in gastric cancer tissues and cell lines. Functionally, it promoted tumor proliferation and shaped the tumor microenvironment, facilitating immune escape in a CD8+ T cell-dependent manner. Mechanistically, hsa_circ_0136666 acted as a sponge for miR-375-3p, thereby upregulating PRKDC, modulating immune checkpoint proteins, and promoting PD-L1 phosphorylation to prevent its degradation. This process induced PD-L1 aggregation and suppressed immune activity, impairing anti-tumor immune responses. Therapeutically, LNP-siRNA targeting hsa_circ_0136666 enhanced the efficacy of anti-PD-L1 treatment and reduced immune evasion. These findings identify hsa_circ_0136666 as an oncogenic circRNA in gastric cancer that drives PD-L1 phosphorylation through the miR-375/PRKDC axis, promoting immune escape. This study uncovers a novel pathogenic mechanism, highlights hsa_circ_0136666 as a potential immunotherapeutic target, and provides a rationale for improving anti-PD-L1 therapy in gastric cancer.
