Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy
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.
Authors
- Simon Jackson
- Junedh Amrute (ORCID: https://orcid.org/0000-0002-6851-0168)
- Kory J. Lavine (ORCID: https://orcid.org/0000-0003-1948-9945)
- Ingrid C. Rulifson (ORCID: https://orcid.org/0000-0003-3251-3989)
- Xianglong Zhang (ORCID: https://orcid.org/0000-0003-0977-5673)
- Tracy Yamawaki (ORCID: https://orcid.org/0000-0002-7716-5650)
- Danielle Pruitt
- Caroline Chou
- Andrea Bredemeyer (ORCID: https://orcid.org/0000-0003-2970-5998)
- Frank M. Bengel (ORCID: https://orcid.org/0000-0003-4529-7963)
- Sidrah Maryam
- Wen-Ling Lin (ORCID: https://orcid.org/0000-0001-6524-9171)
- Thomas Quertermous (ORCID: https://orcid.org/0000-0002-7645-9067)
- Devin L. Wakefield (ORCID: https://orcid.org/0000-0002-0914-0558)
- Brandon Ason
- Atilla D. Kovács
- Vishnu Chintalgattu (ORCID: https://orcid.org/0000-0002-4766-5400)
- Y. Liu
- Melissa M. Thomas (ORCID: https://orcid.org/0000-0003-4636-0901)
- Jixin Cui
- Xin Luo (ORCID: https://orcid.org/0000-0003-1641-5713)
- Steven Yang (ORCID: https://orcid.org/0000-0002-5168-4858)
- Scott D. Martin (ORCID: https://orcid.org/0000-0003-1263-5014)
- Gyu Seong Heo (ORCID: https://orcid.org/0000-0001-6200-4742)
- Chen Wang (ORCID: https://orcid.org/0000-0003-3778-2782)
- In-hyuk Jung
- Daniel Kreisel
- Kevin D. Cook
- Johanna Diekmann
- Rafael Kramann
- Roger S-Y Foo
- Chi-Ming Li
- David Grunert
- Paul Cheng
- Nathan O. Stitziel
- Sikander Hayat
- Jose Barreda
Institutions
- James S. McDonnell Foundation (US)
- Amgen (United States) (US)
- Washington University in St. Louis (US)
- Cardiovascular Institute of the South (US)
- Erasmus MC (NL)
- Medizinische Hochschule Hannover (DE)
- Mallinckrodt (United States) (US)
- National University Health System (SG)
- Institute of Molecular and Cell Biology (SG)
- RWTH Aachen University (DE)
- Erasmus University Rotterdam (NL)
- Stanford University (US)
Publication Details
- Journal
- Science
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1126/science.adx1736
- Citations
- 2
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 48.39