A Clinical Selection Framework for FAP‐Targeted Radiopharmaceuticals: From Diagnosis to Therapy

ABSTRACT

Fibroblast activation protein (FAP) is frequently overexpressed on cancer‐associated fibroblasts across a broad range of epithelial malignancies while showing limited expression in most normal adult tissues, making it an attractive target for cancer theranostics. This review proposes a conceptual clinical selection framework to guide the potential application of FAP‐targeted radiopharmaceuticals. Three molecular platforms, including small‐molecule FAP inhibitors (FAPIs), antibody‐based/nanobody‐based agents, and peptide‐based ligands, were systematically compared according to pharmacokinetics, tumor retention, and available clinical evidence. Small‐molecule FAPIs enable high‐contrast PET imaging, with reported staging changes in approximately one‐third of patients, but their therapeutic application is limited by short tumor retention and insufficient absorbed dose. Antibody‐based platforms provide prolonged circulation that may support α‐emitter therapy but require careful consideration of dosimetry and hematologic toxicity, whereas peptide‐based agents such as FAP‐2286 offer an intermediate pharmacokinetic profile with favorable tolerability. Three priority areas were identified: overcoming FAP heterogeneity (∼18% eligibility), standardizing dosimetry, and expanding α‐emitter accessibility. This review proposes a triage framework for platform selection and highlights rational combinations with immune checkpoint inhibitors as a promising strategy for improving the therapeutic potential of FAP‐targeted radioligand therapy. FAP‐targeted radiopharmaceuticals represent an emerging theranostic strategy with promising diagnostic applications and evolving therapeutic potential.