DDDR-44. Inducing Senolysis by Tumor Suppressive microRNA to Enhance Oncolytic Virus Efficacy for Glioblastoma

Abstract Oncolytic virus (OV) therapy, particularly oncolytic herpes simplex virus-1 (oHSV), has emerged as a promising strategy for treating incurable malignant human cancers, including glioblastoma (GBM), one of the most aggressive and treatment-resistant brain tumors with limited therapeutic options and poor patient outcomes. However, its efficacy is often hindered by intrinsic tumor resistance mechanisms accompanied by increased Akt/mTOR signaling axis. Conventional pharmacological inhibition of Akt was shown to modestly sensitize to OV therapy, but often leads the cancer cells into a state of senescence, avoiding apoptotic cell death. While clinical trials have explored how to induce cell death of the therapy-induced senescent cancer cells, called “senolysis,” most senolytic approaches still focus on inducing non-immunogenic apoptosis. OV therapy presents a promising senolytic solution by inducing tumor-specific immunogenic necrosis and activating adaptive anti-tumor immune responses. Recent studies have highlighted the role of microRNAs (miRNAs) in modulating tumor progression and their therapeutic sensitivity through the inhibition of oncogenic miRNAs or the induction of tumor suppressive miRNAs. Our recent studies identified that miR-433-3p, a potential tumor suppressive miRNA, can significantly sensitize GBM tumor cells to oHSV infection and replication by inducing non-apoptotic senolysis through the suppression of oHSV-induced survival signaling pathways, such as FYN/FAK/Akt signaling axis. We further discovered that the activation of the mTOR pathway is crucial for the miR-433-3p-induced senolysis after oHSV treatment. In summary, this study represents the first preclinical exploration of a senolytic combination of oHSV therapy with tumor suppressive miRNA to enhance viro-immunotherapy in GBM. Our results will improve our understanding of senescence-oHSV interactions in cancer therapy and enable the development of a new therapeutic modality using the senolytic combination.