The value of fibroblast activation protein inhibitor-based radionuclide theranostics in sarcoma: a systematic review

Sarcomas represent a heterogeneous group of malignant neoplasms arising from mesenchymal tissue and remain challenging to diagnose and treat. Fibroblast activation protein (FAP), highly expressed in the tumor microenvironment, has emerged as a attractive target for molecular imaging. This review aims to evaluate the role of fibroblast activation protein inhibitors (FAPI) in sarcoma diagnosis and therapy. Following PRISMA guidelines, we searched PubMed, Embase, and Web of Science for studies published between 2018 and 2025 investigating FAPI in sarcoma imaging or treatment. Diagnostic study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Twelve studies comprising 398 patients met inclusion criteria. Six diagnostic studies (361 patients, 2,477 lesions) reported a pooled detection rate of 89.7% for all sarcoma lesions and 91.3% for distant metastases with FAPI positron emission tomography (PET), higher than [¹⁸F]fluorodeoxyglucose (FDG) PET (72.1% and 74.0%, respectively). In high-grade sarcomas, the mean/median maximum standardized uptake value (SUVmax) for FAPI PET ranged from 9.5 to 30.2; in low-grade tumors, from 6.4 to 21.1. Five therapeutic studies involving 34 patients assessed FAPI radionuclide therapy (RLT) using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), showing a disease control rate of 64.7%. grade ≥ 3 adverse events occurred in only two patients. FAPI PET demonstrates clear advantages over [¹⁸F]FDG PET for systemic lesion detection and may improve sarcoma staging accuracy. FAPI RLT shows great promise as a safe and effective treatment modality. Further studies are needed to confirm its usefulness in grading, staging, and treating sarcoma.