STING promotes CD8 T-cell cardiotropism and fibrosis from distinct cellular compartments in doxorubicin cardiomyopathy

AIMS: Doxorubicin (DR), a widely prescribed chemotherapy, has an unfortunate side effect of cardiotoxicity resulting from DNA damage and cardiac cell death. Cardiac atrophy, fibrosis and a cytotoxic CD8+ T-cell response, alongside increased cardiac and circulating interferon-inducible chemokines are hallmarks for DR cardiotoxicity. METHODS AND RESULTS: We discovered that the activation of the stimulator of interferon genes (STING) in several distinct cardiac cell compartments is central to CD8+ T-cell cardiotropism and DR cardiotoxicity. DR activates STING in cardiac fibroblasts, endothelial cells (ECs), and myeloid cells in vivo and in vitro. Myeloid STING is required for CD8+ T-cell activation and cardiotropism, whereas EC-STING mediates CD8+ T-cell cardiotropism towards CXCL9/10 and transendothelial migration. In contrast, cardiac fibroblast STING is dispensable for the cardiac CD8+ T-cell immune response but drives fibroblast transformation. We report CXCR3+ T cells and CXCL9/CXCL10 are more abundant in the hearts of DR cardiotoxicity patients. CONCLUSION: Our work positions STING as a cell-specific driver of CD8+ T-cell cardiac inflammation and fibroblast activation in DR cardiotoxicity.