Fang Yao, Li Wang
Cardiovascular diseases (CVDs) remain the leading cause of global mortality, perpetuated by pathological remodeling refractory to current pharmacotherapy. Recent single-cell atlasing has identified fibroblast activation protein (FAP) as a convergent marker of pathogenic stromal cells across disparate cardiovascular pathologies. In cardiac fibrosis, FAP demarcates myofibroblasts driving extracellular matrix (ECM) deposition, whereas in atherosclerosis, it marks modulated smooth muscle cells (modSMCs) mediating plaque instability. This review synthesizes emerging evidence to establish a precision cardio-immunology framework. We first characterize FAP not merely as a serine protease, but as a multifaceted integrative node aligned with TGF-β and PI3K/AKT pathways. We then systematically compare the expanding repertoire of FAP-targeted modalities, ranging from cytotoxic CAR T cells and transient bispecific engagers (BiTEs) to tolerogenic dendritic cells, and propose that therapeutic persistence must align with disease kinetics. Specifically, we suggest the use of durable CAR T cells in chronic fibrosis and transient BiTEs for acute plaque stabilization. Finally, we address translational challenges, including FAP’s context-dependent effects, and discuss logic-gated switches to improve the therapeutic index. This review offers a kinetic-matching roadmap for cardiovascular remodeling beyond conventional symptomatic relief.