Conventional targeted therapies have shown limited success in extending survival for gastric cancer patients, primarily owing to off-target toxicities and mechanisms of tumor immune evasion. Circular RNAs are abundantly present in tumor tissues, serving as potential biomarkers and promising therapeutic targets. The role of hsa_circ_0136666 in driving gastric cancer cell proliferation was examined using Western blotting, quantitative real-time PCR (qRT-PCR), fluorescence in situ hybridization (FISH), and flow cytometry. Tumor immune evasion processes in tumor-bearing mouse models were assessed using tissue immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and flow cytometry. Differential expression of circRNAs in clinical specimens was evaluated via tissue microarray FISH. The ability of siRNA to enhance the effectiveness of anti-PD-L1 therapy and modulate the immune microenvironment was tested using co-administration. We showed that hsa_circ_0136666 is broadly and strongly expressed in gastric cancer tissues and cell lines. Functionally, it stimulated tumor cell proliferation and shaped the tumor microenvironment, facilitating immune escape in a manner reliant on CD8+ T cells. Mechanistically, hsa_circ_0136666 acted as a sponge for miR-375-3p, thereby elevating PRKDC levels. This led to PD-L1 phosphorylation, which prevented its degradation, promoted PD-L1 clustering, and suppressed immune activity, ultimately weakening anti-tumor immune responses. Therapeutically, LNP-delivered siRNA significantly boosted the efficacy of anti-PD-L1 agents and curtailed immune evasion. These findings highlight the tumor-promoting role of hsa_circ_0136666 in gastric cancer, driving PD-L1 phosphorylation via the miR-375/PRKDC pathway, thereby enabling immune escape. The study identifies a novel pathogenic mechanism in gastric cancer, positions hsa_circ_0136666 as a new immune-related target, and offers a foundation for improving anti-PD-L1 treatment outcomes in this malignancy.
