PROJECT SUMMARY Whereas it is long known that immune responses are pivotal to the heart’s reaction to stress, our understanding of those events in myocardial remodeling occurring in response to afterload stress is limited. Recently, we reported a pivotal role for cGAS-STING (cyclic GMP-AMP Synthase-Stimulator of Interferon Genes) in myocardial infarction. Going forward, we uncovered evidence for a novel role of cGAS-STING in load-induced cardiac hypertrophy and failure. We have discovered that loss of STING – surprisingly – exacerbated hypertrophy and fibrosis triggered by pressure stress. We observed a marked increase in CD86, CD80, and CD28, signatures of T cell activation, and cytotoxic T cell proliferation in STING-deficient hearts. In addition, CD103+ cells, representing the antigen presenting dendritic cell population, are doubled in response to pressure overload in STING-deficient heart compared to WT. Furthermore, our data reveal that STING is expressed in cardiac immune cells and fibroblasts, in contrast to cGAS, which is present predominantly in macrophages. STING’s broader scope of distribution suggests a more prominent role in cardiac hypertrophy. Based on this evidence, we propose studies focusing on STING to dissect the underlying molecular circuitry. We hypothesize that STING regulates T cell activation and antigen presentation, adaptive immune processes crucial to myocardial remodeling and development of heart failure, in the setting of afterload stress. Here, we propose studies to define and manipulate STING-dependent regulation of T cell function in afterload stress- induced cardiac remodeling, focusing on both ventricular hypertrophy and ultimate contractile dysfunction. With an eye toward ultimate translation to patients with heart disease, we also capitalize on pharmacological tools, some of which are currently being tested in clinical trials in cancer, to manipulate STING signaling. The cGAS-STING pathway-mediated immune response, spanning both innate and adaptive elements, represents an entirely novel mechanism of cardiac remodeling and failure. Furthermore, knowledge acquired during these studies is likely to shed light on other forms of heart disease and elucidate cardiac complications of cancer immunotherapy. We propose a comprehensive series of studies to define the role of cGAS-STING in afterload-induced cardiac remodeling. These studies interlace at many points with work proposed in the 3 other Projects. We have developed multiple points of bidirectional collaboration across the entire Program, sharing of reagents and insights, as well as benefit from extensive use of the Core facilities.