Junedh Amrute, Junedh M. Amrute, In-Hyuk Jung, In-Hyuk Jung, Tracy Yamawaki, Wen-Ling Lin, Andrea Bredemeyer, Johanna Diekmann, Sikander Hayat, Xianglong Zhang, Devin L. Wakefield, Xin Luo, Sidrah Maryam, Gyu Seong Heo, Steven Yang, Chang Jie Mick Lee, Chen Wang, Caroline Chou, Christoph Kuppe, Kevin D. Cook, Atilla D. Kovács, Vishnu Chintalgattu, Danielle Pruitt, Jose Barreda, Nathan O. Stitziel, Paul Cheng, Yongjian Liu, Rafael Kramann, Daniel Kreisel, Roger S.-Y. Foo, Ingrid C. Rulifson, Scott Martin, David Grunert, Thomas Quertermous, Jixin Cui, Thomas Quertermous, Frank M. Bengel, Simon Jackson, Chi-Ming Li, Brandon Ason, Kory J. Lavine
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.