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

Summary

Using multiomic single-cell and spatial analyses of human coronary plaques, the authors identify fibroblast activation protein (FAP) as a robust marker of modulated VSMCs. Mouse lineage tracing supports VSMC origin of FAP+ cells, and FAP-directed immunotherapy enables selective targeting of these modulated states, suggesting a therapeutic avenue to reshape plaque biology.

Key Findings

• Multiomic single-cell and spatial profiling across 27 human coronary arteries identified FAP as a marker of modulated VSMCs.
• Mouse lineage tracing supported a VSMC origin of FAP+ cells within plaques.
• FAP-directed immunotherapy enabled selective targeting of modulated VSMCs in preclinical models.
• The study links VSMC state transitions to a potentially druggable surface target in human atherosclerosis.

Clinical Implications

If validated, FAP-targeted imaging/therapeutics could identify and modulate high-risk plaques by selectively eliminating or reprogramming modulated VSMCs, complementing current lipid-lowering and anti-inflammatory approaches.

Limitations

• Abstracted human sample size is modest (27 arteries) and from advanced disease, which may limit generalizability across stages and beds
• Clinical efficacy and safety of FAP-directed immunotherapy remain to be demonstrated in humans

Future Directions

Develop FAP-targeted imaging probes and therapeutic agents; evaluate efficacy and safety in large-animal models and early-phase human trials; investigate synergy with lipid-lowering and anti-inflammatory therapies.