Modified Vaccinia Virus Ankara Selectively Targets Human Cancer Cells With Low Expression of the Zinc‐Finger Antiviral Protein

Oncolytic viruses are emerging as promising cancer therapeutic agents, with several poxviruses, including vaccinia virus (VACV) and myxoma virus, showing significant potential in preclinical and clinical trials. Modified vaccinia virus Ankara (MVA), a laboratory-derived VACV strain approved by the FDA for mpox and smallpox vaccination, has been shown to be incapable of replicating in human cells unless zinc finger antiviral protein (ZAP) is repressed. Notably, ZAP deficiency is prevalent in various cancer types. We hypothesized that MVA could selectively target and replicate in ZAP-deficient cancer cells. Our study examined MVA's replication across multiple cancer cell lines with varying ZAP expression levels, revealing that MVA replicates more efficiently in cells with lower ZAP expression. Additionally, we assessed MVA's oncolytic potential using a xenograft mouse model, where cancer cells were transplanted into immunodeficient mice. The data demonstrated that MVA significantly reduced tumors with lower ZAP expression without causing morbidity in nude mice. These findings suggest that MVA holds promise for further development as a targeted therapy for ZAP-deficient cancers.