Engineered T cell therapy for the treatment of cardiac fibrosis during chronic phase of myocarditis

<b>Background</b>: Chronic myocarditis (CMYO) progresses to fibrosis and heart failure, yet no therapies effectively target fibrosis. Fibroblast activation protein (FAP) marks pathogenic myofibroblasts, but its therapeutic potential remains unexplored in inflammatory settings. <b>Methods</b>: Using bulk/scRNA-seq of human myocarditis samples, we identified FAP as a fibrosis-specific marker. We engineered FAP-targeted CAR-T (FAP.CAR-T) cells and tested their efficacy in autoimmune (EAM) and viral (CVB3) myocarditis models. Human cardiac organoids (hCOs) treated with IL-17A modeled inflammatory fibrosis. <b>Results</b>: FAP expression correlated with fibrosis severity in patients (r = 0.96, P = 0.0028). In EAM and CVB3 models, FAP.CAR-T cells reduced fibrosis by 65% and 55%, respectively (P < 0.001), restored ejection fraction to higher than 65%. hCOs treated with FAP.CAR-T cells showed 55% less fibrosis (P < 0.05). No toxicity was observed in healthy mice. <b>Conclusions</b>: FAP.CAR-T cells eliminate fibrosis-driving myofibroblasts, reversing cardiac dysfunction in chronic myocarditis. This strategy, validated in human organoids, offers translatable immunotherapy for fibrosis-driven heart disease.