Abstract

Glioblastoma is a highly aggressive and devastating primary brain tumor that is resistant to conventional therapies. Oncolytic viruses represent a promising therapeutic approach for glioblastoma by selectively lysing tumor cells and eliciting an anti-tumor immune response. However, the clinical efficacy of oncolytic viruses is often hindered by challenges such as short persistence, host antiviral immune responses, and T cell dysfunction. We have developed a novel therapeutic strategy by "dressing" oncolytic viruses with anti-PD-1 antibodies and alendronate (PD-1/Al@OV) to prevent premature clearance of the oncolytic viruses and enhance T cell function, thereby improving immunotherapy outcomes against glioma. We found that in the high reactive oxygen species environment of the tumor, PD-1/Al@OV disassembled to release oncolytic viruses, anti-PD-1, and alendronate. The released anti-PD-1 blocked the PD-1/PD-L1 pathway, activating T cells; the alendronate eliminated tumor-associated macrophages, increasing the concentration of oncolytic viruses; and the oncolytic viruses directly lysed cancer cells, enhancing intratumoral T cell infiltration. This approach effectively improved the immunosuppressive microenvironment of glioblastoma and achieved a robust anti-tumor effect. Consequently, this study presents a novel strategy for immune combination therapy and the improvement of the glioblastoma immune microenvironment, thereby offering new prospects for the clinical application of oncolytic viruses.