Cellular transformation is accompanied with loss of fundamental cellular processes, such as the ability of efficiently fight viral infection. As a result, tumor cells are often more susceptible to viral infection and lysis than healthy cells. Virotherapy takes advantage of the inability of cancer cells to effectively contrast viral infection. Virotherapy is based on the administration of lytic viruses with selective tropism for cancer cells (oncolytic viruses) and showed promising results in clinical trials for several tumor indications, including prostate cancer. However, the response was far from complete (<50% in prostate cancer) and it is not clear why some patients responded to therapy and some did not. In an effort to determine potential contributors to oncolytic virus sensitivity, we recently discovered that the immune protein PD-L1 enhances the lytic potential of the oncolytic virus VSV in a mouse prostatic cancer cell line, TRAMP-C2. We are requesting support to Ride for Dad to determine the molecular pathways responsible for the PD-L1-dependent enhancement of VSV lytic ability. Our discoveries could provide a new biomarker for virotherapy, PD-L1 expression, and identify novel targets to enhance the efficacy of oncolytic viruses in prostate cancer.