Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy.
basic_science · Level V
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- Record sourced from PubMed, PMID 41610194.
- Also identified by DOI 10.1126/science.adx1736.
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Abstract
Vascular smooth muscle cell (VSMC) diversification drives atherosclerotic coronary artery disease (CAD). 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<sup>+</sup> cells originate from <i>Myh11</i><sup>+</sup> VSMCs, and FAP PET imaging in CAD patients showed plaque uptake. FAP<sup>+</sup> cells 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.