Chimeric antigen receptor (CAR) T cell therapy for atherosclerosis

Foamy macrophages are central drivers of atherosclerotic plaque progression, yet no strategy exists to selectively eliminate these pathogenic cells. Here, we identify TREM2 as a conserved surface marker of foamy macrophages across human and mouse atherosclerotic tissues by integrated single-cell transcriptomic analysis. We generated TREM2-targeting chimeric antigen receptor (CAR) T cells and showed that they mediate potent, antigen-dependent cytotoxicity against TREM2-positive target cells in vitro. In a human vessel organoid system, TREM2 CAR T cells selectively depleted macrophage-like cells while preserving vascular integrity. In vivo, TREM2 CAR T-cell therapy reduced plaque area, necrotic core formation, and lesional TREM2+ macrophage accumulation in Apoe⁻/⁻, Ldlr⁻/⁻ and AAV8-PCSK9 mouse models of atherosclerosis, without affecting plasma lipid levels or inducing overt toxicity. Our results provide proof of concept that foamy macrophages are therapeutically targetable and establish cellular immunotherapy as a potential treatment for atherosclerosis.