ITGA11-targeted CAR macrophages attenuate cardiac fibrosis and improve functional recovery post-myocardial infarction

Background Pathological cardiac fibrosis following myocardial infarction (MI) is a critical driver of heart failure, yet clinical interventions targeting activated myofibroblasts remain scarce. Although Fibroblast Activation Protein (FAP) is a widely utilized chimeric antigen receptor (CAR) target, its systemic expression in healthy tissues—particularly bone marrow and skeletal muscle—presents substantial risks of off-target toxicity. Consequently, identifying more lineage-specific markers is imperative. In this study, we identify Integrin alpha11 (ITGA11) as a highly specific candidate for targeting activated cardiac fibroblasts. Purpose To evaluate the therapeutic potential and safety of ITGA11-targeted CAR macrophages (ITGA11-CAR-Ms) in mitigating MI-induced fibrosis and remodeling. Methods ITGA11 expression kinetics were characterized in a mouse model of MI induced by permanent left anterior descending (LAD) artery ligation. ITGA11-CAR-Ms were generated via lentiviral transduction of bone marrow-derived macrophages (BMDMs). Specific phagocytic activity was validated in vitro using ITGA11-expressing targets. For in vivo assessment, ITGA11-CAR-Ms were adoptively transferred into mice 3 days post-MI. Cardiac function was monitored via echocardiography, while fibrosis was quantified using Masson’s trichrome staining and collagen volume fraction (CVF) analysis. Results ITGA11 expression was negligible in healthy cardiac tissue but underwent progressive and significant upregulation starting 7 days post-MI, localizing specifically to activated α-SMA+ myofibroblasts. In vitro, ITGA11-CAR-Ms exhibited robust and specific phagocytic activity toward ITGA11+ cells. In vivo, adoptive transfer at day 3 significantly restricted the expansion of the fibrotic area and reduced CVF compared to control groups. Furthermore, ITGA11-CAR-M therapy markedly improved left ventricular ejection fraction (LVEF) and fractional shortening (FS). Safety evaluations 2 weeks post-treatment demonstrated no evidence of off-target toxicity in major organs (liver, lung, and kidney) or systemic inflammatory cytokine responses. Conclusions This proof-of-concept study demonstrates that ITGA11-CAR-Ms effectively target and clear activated myofibroblasts to alleviate cardiac fibrosis and preserve contractile function. Our findings highlight the therapeutic potential of engineered macrophages in treating post-MI remodeling and offer a novel, potentially safer immunotherapeutic strategy for fibrotic heart diseases.Figure-1Figure-2