Targeting Fibroblast Activation Protein for Precision Medicine

Conspectus

The advancement of precision medicine depends critically on well-defined molecular targets. Pathologically activated fibroblasts drive disease progression in cancer, fibrosis and chronic inflammation through sustained inflammation, extracellular matrix remodeling and pathological microenvironment formation. Among available markers, fibroblast activation protein (FAP) stands out due to its selective overexpression in diseased tissues versus minimal expression in healthy organs. This unique profile makes FAP a promising target for molecular imaging and targeted therapy, enabling precision theranostics across both oncological and nononcological diseases.

FAP-targeted theranostics originated from the lead compound PT-100, which established the core pharmacophore. Subsequent key advance was the replacement of the boronic acid warhead with a cyano group, along with the introduction of fluorine and quinoline moieties, yielding the UAMC-1110 scaffold. This scaffold exhibits improved bioactivity and favorable pharmacokinetics. Systematic modification of the quinoline side chain and conjugation with chelators have allowed efficient radiolabeling, positioning radiolabeled FAP inhibitors as promising tools for precision theranostics. However, continued optimization of UAMC-1110-derived probes to enhance their stability, affinity, tumor retention, and cellular uptake, together with integration into advanced strategies such as nanomedicine, remains essential not only for refining FAP-targeted precision medicine but also for expanding its applications beyond oncology to nononcological diseases.

Unlike previous reviews, this Account organizes the field around a unified chemical design language, following a “rational design-pharmacokinetics-translational validation” paradigm. After delineating the core biological functions of FAP-expressing fibroblasts in disease pathogenesis, we systematically examine the rapid advancement of radionuclide-labeled FAPIs, including optimization of linkers, chelators, and albumin-binding moieties, along with multimerization strategies, which significantly enhanced the pharmacokinetic profiles. Key innovations in the field include three strategic approaches. First, the albumin-binding therapeutic agent [177Lu]Lu-EB-FAPI achieves prolonged tumor retention and promising efficacy. Second, multimerization strategies have yielded bivalent and tetrameric FAPI constructs, which exhibit superior tumor accumulation. Third, heterodimeric probes such as [68Ga]Ga-FAPI-RGD and [68Ga]Ga-FAPI-LM3 enable dual targeting of FAP along with integrin αvβ3 or somatostatin receptor SSTR2, thereby addressing tumor heterogeneity and enhancing lesion detectability. Subsequently, the application scope of FAPI-based imaging has been expanded from oncology to nononcological diseases. The value of this technique in visualizing dynamic remodeling processes across key pathologic conditions has been established, offering quantitative assessment beyond the reach of standard modalities. Furthermore, we review recent advances in diverse FAP-targeted therapeutic strategies, including nanomaterials, CAR-T cells, and vaccines, and offer a forward-looking perspective on both the potential and the ongoing challenges of FAP as a cross-disease precision theranostic platform.