Ovarian cancer is the sixth most prevalent cancer in women and the most lethal of the gynecologic malignancies. Treatments have comprised the use of immunotherapeutic agents as well as oncolytic viruses, with varying results for reasons that remain to be clarified. To better understand the mechanisms that may help predict treatment outcome, we have evaluated innate immune signaling in select ovarian cancer cell lines, governed by the Stimulator of Interferon Genes (STING), which controls self or viral DNA-triggered cytokine production. Our results indicate that STING-dependent signaling is habitually defective in majority of ovarian cancer cells examined, frequently through the suppression of STING and/or the cyclic dinucleotide (CDN) enzyme Cyclic GMP-AMP synthase (cGAS) expression, by epigenetic processes. However, STING-independent, dsRNA-activated innate immune cytokine production, which require RIG-I/MDA5, were largely unaffected. Such defects enabled ovarian cancer cells to avoid DNA damage-mediated cytokine production, which would alert the immunosurveillance system. Loss of STING signaling also rendered ovarian cancer cells highly susceptible to viral oncolytic γ34.5 deleted-HSV1 (Herpes simplex virus) infection and . IMPLICATIONS: STING signaling evaluation in tumors may help predict disease outcome and possibly dictate the efficacy of oncoviral and other types of cancer therapies.