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 effectiveness 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 expression, 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 and Discussion: 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 expression 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 siRNA-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 glioblastoma.