Clinical research and application progress of fibroblast activation protein targeted molecular imaging
[Background]Cancer-associated fibroblasts(CAFs)are a major component of the tumor microenvironment(TME)and secrete growth factors,inflammatory ligands,and extracellular matrix(ECM),which promote tumor proliferation,therapy resistance,and immune exclusion.Fibroblast activation protein(FAP)is overexpressed on the cell membrane and in the stroma of CAFs in approximately 90％of epithelial neoplasms.However,it is not expressed in normal fibroblasts,normal epithelial cells,or the stroma of benign epithelial tumors.Therefore,FAP has emerged as a novel cancer target due to its wide distribution across numerous cancer types.[Progress]FAP-targeted imaging with radioiodine-labeled monoclonal antibody F19 was the first step in moving the concept of FAP-directed tumor stromal targeting from the preclinical phase to in vivo evaluation.FAP-targeting has been reported using a variety of approaches,including vaccines,chimeric antigen receptor(CAR)T cells,and peptide drug complexes.FAP inhibitors(FAPIs)with high selectivity and chemical stability,represent promising strategies for the development of FAPIs.Studies conducted using FAPIs,which have favorable radiopharmacokinetics,have initiated to the clinical application of FAP-targeted theranostics in various tumors.18F-fluorode-oxyglucose(18F-FDG)is the most widely used tracer for positron emission tomography(PET)imaging in the field of oncology.However,nonspecific and physiological radiotracer uptake in crucial organs reduces diagnostic accuracy in many cases,which has substantial disadvantages for various applications.FAPI PET is independent of glucose metabolism,leading to a low background signal in the brain,liver,nasopharyngeal,oral mucosa,and gastrointestinal tract.Additionally,FAPI PET can be used without any dietary preparation and provides stable tracer uptake from 10 min to 3 h after administration.Consequently,the clinical interest in FAPI imaging has shown an explosive increase,and FAPI imaging has been explored for various purposes in different clinical settings,yielding promising results.This review summarizes the literature on the value of FAPI radiopharmaceuticals for PET imaging in oncological disease and non-oncological disease,and discusses its broader clinical implementation.In addition,our qualitative summary of the literature can guide future research directions,inform medical guidelines,and support optimal clinical decision-making.In this review,we aim to provide an overview of the clinical applications of FAP-based radiopharmaceuticals for the diagnosis and therapy in cancers and other benign conditions.[Perspective]FAPI variants labeled with radionuclides have shown impressive results in a broad spectrum of cancers and benign diseases,potentially opening a new chapter in the molecular imaging of oncological disease and non-oncological disease.Overall,considering radio tracer uptake and the tumor-to-background ratio,FAPI PET usually demonstrates an equal or higher detection rate of primary tumors and/or metastatic lesions than 18F-FDG PET.However,base on current evidence,FAPI PET imaging is more accurately positioned as"a supplement"to 18F-FDG rather than ending the hegemony of 18F-FDG in oncology.Well-designed clinical trials with larger patient populations are required to further define the role of this diagnostic agent.In addition to CAFs,high FAP expression is associated with fibrosis,arthritis,atherosclerosis,and autoimmune diseases.Thus,FAPI uptake in non-malignant diseases must be carefully identified.Overall,FAPI-based imaging and cancer therapy have become highly active research fields in recent years.We look forward to future studies and the rapid translation of the most promising FAPI ligands into the clinical arena to benefit patients with various types of cancer.
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