Li and colleagues identified RhoA as a “redox rheostat” governing mitochondrial dynamics during oncolytic virotherapy and thereby engineered rNDV-RHOA, an NDV-based oncolytic virus overexpressing RhoA. This tumor-targeted RhoA overexpression synergizes oxidative stress and viral oncolysis, transcending conventional oncolysis by surmounting tumor heterogeneity through exploiting inherent tumor redox dependency.