Innate Immunity and Viral Oncolytic Agents: It has been noted that normal cells exhibit resistance to virus infection compared to cancer cells. We postulated that during the transformation process, cancer cells may have acquired defects in their intrinsic innate immune signaling pathways, which render them susceptible to infection (Balachandran et al., Immunity 2000, Balachandran and Barber IUBMB Life 2000). We and others have now characterized many types of cancer cells and found that a large majority exhibit an impaired capacity to produce type I interferon, in part through harboring defective innate immune signaling (Balachandran and Barber, Cancer Cell, 2004; Xia et al, Cancer Research 2016). Our observations lead to us to pioneer the use of viruses such as vesicular stomatitis virus (VSV) as therapeutics for the treatment of cancer. Such studies enabled us, with collaborators, to initiate Phase I and soon Phase II trials using recombinant VSV, an RNA virus, as an oncolytic agent (Fernandez et al., J. of Virol 2002; Obuchi et al., 2003). Recombinant herpes simplex virus (HSV) a DNA virus, is also being used as an oncolytic therapy. Our discovery of the STING pathway and subsequent studies related to STING signaling in cancer cells (or lack of) has shed considerable light into why certain tumors may be susceptible or not to HSV-mediated oncolysis. For example, our investigations indicate that during the transformation process, STING signaling is suppressed (typically by epigenetic silencing of cGAS or STING; Xia et al Cell Reports, 2016). Evidence indicates that carcinogens induce DNA damage and cause the leakage of genomic DNA into the cytosol, which activates STING signaling and cytokine production (Ahn et al., Nature Communications 2014). This alerts the immunosurveillance system which attempts to eliminate the damaged cells, likely by phagocytosis. This process also generates anti-tumor T cell activity (Ahn et al., Cancer Cell, 2018). Thus, suppression of STING signaling, while helping to avoid anti-tumor immune responses, also leaves such cells susceptible to viral oncolysis. Our lab continues to evaluate mechanisms of viral oncolysis and to evaluate the use of viruses as therapeutics to treat cancer.