CAR-based immunotherapy for cardiac fibrosis: A new therapeutic frontier

Cardiac fibrosis is a central pathological hallmark of diverse cardiovascular disorders, driving myocardial stiffening, ventricular dysfunction, and the progression of heart failure. Following cardiac injury, resident quiescent fibroblasts activate into pro‑fibrotic myofibroblasts, which overproduce extracellular matrix and perpetuate maladaptive cardiac remodeling. Current clinical interventions fail to specifically target pathological cells or reverse established fibrosis, leaving a major unmet therapeutic need. Chimeric antigen receptor (CAR)-based immunotherapy, originally revolutionizing oncology, has emerged as a precision strategy to selectively recognize, eliminate, or regulate cardiac fibrotic drivers. Its application to cardiac fibrosis, primarily through targeting activated fibroblasts and fibrotic niches, shows preclinical promise in halting or reversing disease. Although most evidence remains preclinical, early clinical translation has begun for selected fibrosis-targeted immunomodulatory cell therapies. This Review synthesizes advances in CAR-based immunotherapy for cardiac fibrosis, focusing on disease pathobiology, validated and emerging target antigens, diverse cellular platforms, preclinical evidence, and the key barriers to safe and effective clinical translation.