Comparative evaluation of oncolytic viruses reveals opposing preferences for glioblastoma subtypes

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults characterized by poor long-term survival and frequent tumor recurrence, highlighting the urgent need for novel therapeutic strategies. Oncolytic viruses (OVs) preferentially infect and kill cancer cells while stimulating an antitumor immune response. Oncolytic virotherapies have shown encouraging results in preclinical GBM models and some clinical settings. However, high tumor heterogeneity poses a major obstacle. Only a subset of GBM patients responds well, and improvement in survival is usually limited. It is therefore crucial to better understand determinants of OV effectiveness and to consider multiple OVs. Here, we report a comparative analysis of the oncolytic efficacy of 15 clinically relevant viruses across a diverse panel of 14 heterogeneous patient-derived GBM cell lines. Correlation analysis revealed two clusters of viruses with opposing oncolytic activity profiles and opposing preferences for GBM subtypes. Oncolytic activities correlated with expression levels of interferon-, neurodevelopment-, and extracellular matrix-related gene sets, with inverse correlations observed between the two OV groups. Together, these data reveal that diverse viruses share similar determinants of oncolytic activity. Our findings pave the way toward combinatorial or personalized OV therapies in GBM, where tumor subtype could guide selection of the most effective OV.