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Abstract Viruses are completely dependent on host cell machinery for their reproduction. As a result, factors that influence the state of cells, such as signaling pathways and gene expression, could determine the outcome of viral pathogenicity. One of the important factors influencing cells or the outcome of viral infection is the level of oxygen. Recently, oncolytic virotherapy has attracted attention as a promising approach to improving cancer treatment. However, it was shown that tumor cells are mostly less oxygenated compared with their normal counterparts, which might affect the outcome of oncolytic virotherapy. Therefore, knowing how oncolytic viruses could cope with stressful environments, particularly hypoxic environments, might be essential for improving oncolytic virotherapy.