Updated project metadata. Pancreatic ductal adenocarcinoma (PDAC) remains a particularly aggressive disease with few effective treatments. The PDAC tumor immune microenvironment (TIME) has been characterized as immune suppressed. Oncolytic viruses can increase tumor antigenicity via immunogenic cell death (ICD). In this study, tumor-targeting and cytokine-armed vaccinia viruses (vvDD, vvDD-IL2, vvDD-IL15) were used to infect carcinoma cell lines as well as patient-derived primary PDAC cells. In co-culture experiments we tested the cytotoxic response and the activation of human natural killer-(NK-)cells during the oncolytic process.