Tumors and cancer cell lines exhibit varying levels of activation in interferon (IFN) pathways and expression of IFN-stimulated genes (ISGs). This heterogeneity correlates with differential susceptibility to oncolytic viruses (OVs), which exploit impaired IFN responses to replicate in and kill malignant cells preferentially. A current challenge in oncolytic virotherapy (OVT) is to develop strategies that selectively inhibit IFN responses in malignant cells, thereby expanding the therapeutic range of OVs. This study proposes leveraging the vulnerability of tumor cells to BH3 mimetic compounds and caspase-mediated inhibition of IFN responses to enhance OVT in OV-resistant tumors. Analysis of the bladder cancer (BC) cohort from The Cancer Genome Atlas (TCGA) revealed a cluster of antiviral ISGs exhibiting positively correlated expression, and subpopulations of high- and low ISG expressors. A similar pattern was observed in the urinary tract cohort of the Cancer Cell Line Encyclopedia (CCLE), suggesting that this ISG expression profile is regulated in a cell-autonomous manner. We study two BC cell lines, T24 and UMUC3, differing in ISG expression, and SKMEL3 melanoma cells, a non-BC cell line with features similar to T24. T24 and SKMEL3 cells exhibited Janus kinase (JAK)-dependent resistance to the oncolytic orbivirus Epizootic Hemorrhagic Disease Virus Tel Aviv University (EHDV-TAU). Treatment with the BH3 mimetic Abt737 activated caspases, suppressed IFN-mediated antiviral responses, and enabled productive EHDV-TAU infection in tumor cells but not in normal fibroblasts. Mechanistically, Abt737 induced caspase-dependent cleavage of signal transduction Signal Transducer and Activator of Transcription 1 (STAT1) in both cell lines and interferon regulatory factor 3 (IRF3) in T24 cells, suggesting disruption of IFN/JAK/STAT signaling and IFN induction. In these cells, the EHDV-TAU + Abt737 combination increased the plasma membrane exposure of calreticulin and extracellular ATP, markers of immunogenic cell death. In contrast, combining Abt737 with a mutant vesicular stomatitis virus (VSVΔ51M) reduced viral titers, indicating virus-specific effects. This strategy appears optimal for OVs like EHDV-TAU, which thrive in apoptotic environments. Overall, this approach may broaden OVT’s therapeutic reach by leveraging apoptosis to overcome tumor antiviral resistance. In this study, we investigate a novel cancer treatment strategy that combines BH3 mimetics, drugs that trigger cancer cell death, with oncolytic viruses, which selectively infect and kill cancer cells. While promising, virus-based therapies often face resistance due to strong antiviral defenses in some tumors. Focusing on Bladder Cancer (BC), a disease with emerging virus-based treatment options, we analyzed gene expression in BC tumors and cell lines. Our findings reveal distinct subpopulations with either high or low antiviral gene expression, suggesting that some tumors may respond directly to oncolytic viruses. In contrast, others may require a combination approach to overcome resistance. We tested the BH3 mimetic Abt737 in BC and melanoma cells resistant to the novel oncolytic virus EHDV-TAU. Treatment with Abt737 sensitized these cells, but not non-cancerous cells, to viral infection, thereby permitting viral replication. Mechanistically, Abt737 activated enzymes that promote apoptosis and disrupted antiviral defenses. Additionally, the virus-compound combination enhances the immunogenicity of dying cancer cells, potentially supporting long-term tumor control. Interestingly, this sensitization effect was virus-specific, indicating that only certain oncolytic viruses may benefit from this approach. Overall, our results suggest that combining BH3 mimetics with select oncolytic viruses could expand treatment options for resistant cancers by weakening their antiviral defenses and enhancing immune activation.
Bozhdansky et al. (Tue,) studied this question.