Fibroblast Activation Protein-Targeted Theranostics: Current Status in Clinical Development

Fibroblast activation protein (FAP) has attracted growing interest as a promising target for cancer imaging and therapy due to its highly selective expression in the tumor stroma. This review summarizes the current development status of FAP-targeted radioligand therapy based on clinical evidence reported to date. Early therapeutic pipelines utilized quinoline-based compounds such as FAPI-04 and FAPI-46, predominantly investigated for PET imaging, by labeling them with beta-emitting radionuclides. Despite high tumor uptake, these early agents showed limited therapeutic efficacy due to short tumor retention and insufficient intratumoral radiation dose. To overcome this limitation, various structural modifications have been investigated to improve tumor retention, including cyclic peptides, dimers, and albumin binders. Several of these modified agents have been evaluated in clinical studies, showing improved tumor dosimetry while maintaining acceptable normal organ doses and toxicity profiles. However, therapeutic outcomes remain inconclusive, and evidence from large-scale, well-structured studies is still lacking. Currently, a few compounds are under investigation in early-phase clinical trials aimed at regulatory approval for clinical use. Evidence of therapeutic efficacy from those strictly designed clinical trials is awaited.