Enhanced Efficacy of Radiation Therapy against Glioblastoma by Attenuated Salmonella Carrying Co-Expression Plasmids with siRNA-PD-L1 and Endostatin

Background: Glioblastoma (GBM), a common type of brain tumor, is currently treatable through radiation therapy. However, there is room for improvement in the effec-tiveness of treatment. Radiation can lead to an increase in the expression of PD-L1 and VEGF, which might reduce the responsiveness of the tumor to the therapy. This situation underlines the necessity for innovative treatment strategies. Objectives: In this study, we investigated the potential of attenuated Salmonella carrying the co-expressing plasmid siPD-L1-Endo to effectively inhibit PD-L1 and VEGF expres-sion, thereby enhancing the anti-tumor effects of radiation therapy in GBM-bearing mice. Methods: The regulatory mechanisms responsible for the treatment effect were detected by Flow cytometry, Immunohistochemistry, TUNEL, Immunofluorescence, H&E staining, and Western blot assays. Results: Upon administration of attenuated Salmonella carrying siRNA-PD-L1 and co-expressing endostatin plasmids, the results exhibited significant suppression of tumor growth and tumor cell proliferation, as well as a concurrent decrease in PD-L1 and VEGF expression in tumor tissues. Moreover, the treatment led to reduced expression levels of tumor-related proteins p-Stat3, MMP2, Cyclin D1, and PCNA, an increase in the expres-sion of the apoptosis-related protein cleaved-caspase3, facilitated infiltration of CD4+ and CD8+ T cells within tumor tissues, and an elevation of the ratios of CD4+, CD8+ T cells, and NK cells in the spleen of tumor-bearing mice. Conclusion: These findings highlight the ability of attenuated Salmonella carrying siR-NA-PD-L1 and co-expressing endostatin plasmids to effectively modulate PD-L1 and VEGF expression, thus strengthening the anti-tumor immune response in GBM-bearing mice subjected to radiation therapy. This combination therapy approach holds promise as a potential avenue for improving the efficacy of radiation therapy in the treatment of glio-blastoma.