Prostate cancer is currently the second leading cause of cancer death in men in USA. Although surgical intervention and other first-line therapies for prostate cancer have improved over the past decades, there is still no effective cure for patients suffering from advanced/recurrent disease. Prostate cancer, like other cancers, is a heterogeneous disease such that individualized/precision medicine is likely to benefit patients. Our data indicate that a subset of prostate cancer exhibits reduced expression of a protein (cGAS) known to be involved in the response of cells to viral or bacterial infection. Importantly, lower expression of cGAS is correlated with prostate cancer recurrence, suggesting that loss of cGAS reduces efficacy of therapy. Interestingly, low cGAS is associated with poor outcome in lung cancer as well. In this proposal, we present preliminary data strongly supporting novel tumor suppressor roles of cGAS in prostate cancer functioning in individual cancer cells. We will fully investigate the underlying regulatory mechanisms and biological effects of the loss of cGAS in prostate cancer, along with the initial exploration of therapeutic vulnerabilities associated with this dysregulated pathway. We are hopeful that our studies will enable new therapeutic options for prostate cancer patients, with potential relevance to a subset of lung cancer.