Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy
- Junedh M. Amrute
- 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 Kovacs
- 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
- Melissa Thomas
- Jixin Cui
- Thomas Quertermous
- Frank M. Bengel
- Simon Jackson
- Chi-Ming Li
- Brandon Ason
- Kory J. Lavine
2026-01-29
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.