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

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.

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.

Our work positions STING as a cell-specific driver of CD8⁺ T-cell cardiac inflammation and fibroblast activation in DR cardiotoxicity.