Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy

Vascular smooth muscle cell (VSMC) diversification drives atherosclerotic coronary artery disease (CAD), but the mechanisms governing these cell state transitions remain unclear. We applied multiomic single-cell profiling, epitope mapping, and spatial transcriptomics across 27 human coronary arteries, identifying fibroblast activation protein (FAP) as a marker of modulated VSMCs. Lineage tracing in mice indicated that FAP + cells originate from Myh11 + VSMCs, and FAP positron emission tomography imaging in CAD patients showed plaque uptake. FAP + cell states resided in the macrophage-rich neo-intima. Therapeutically, we developed an anti-FAP bispecific T cell engager, which reduced plaque burden and remodeled the stromal–immune microenvironment through T cell clonal expansion. Our study delivers a single-cell and spatial atlas of human CAD, establishes FAP as a marker of modulated VSMCs, and highlights immunotherapy for lipid-independent targets.