Fibroblast Activation Protein-Directed PET: Expanding FAPI Beyond Cancer

Fibroblast activation protein (FAP) has gained clinical interest as a target for imaging and therapy in a spectrum of oncologic diseases in recent years. Yet, FAP expression by activated fibroblasts is not specific to the tumor microenvironment but rather shows tight coupling to pathologic tissue remodeling, chronic inflammation, and fibrosis across a broad spectrum of nonmalignant diseases. This linkage provides a compelling biologic rationale for extending FAP-directed imaging beyond oncologic applications. Indeed, across various cardiac (ischemic heart disease, nonischemic cardiomyopathy, valvular pathology), vascular (atherosclerosis, vasculitis, aneurysm), rheumatologic (interstitial lung disease, inflammatory arthritis, IgG4-related disease), and other conditions, emerging data suggest that FAP-directed PET may serve as an imaging biomarker for active tissue remodeling. Nonetheless, the supporting clinical evidence is derived primarily from early-stage studies and remains largely exploratory at present. FAP-targeted therapies (e.g., FAP-targeting radiopharmaceutical therapies and chimeric antigen receptor T-cells) are also being actively explored outside of oncology in preclinical settings. While further investigation remains needed, FAP-directed PET has the potential to become a valuable addition to fibrosis-driven disease monitoring. Within this context, this Special Series Review highlights the current early evidence and future potential of FAP-directed PET across a variety of nononcologic conditions.