Editorial

An efficacious opportunity for diagnosis and treatment of cancers: Radiolabeled fibroblast activation protein (FAP) inhibitors

Fibroblast activation protein (FAP), a 760 amino acid type II transmembrane glycoprotein belongs to serine protease series, significantly associated with tumor invasion and metastases.¹ It is demonstrated that FAP is expressed in wide ranges of stromal fibro­blasts in more than 90% of epithelial tumor cells in various cancers.^2,3 Overexpression of FAP and increasing of tumor invasion, lower survival, and poor prognosis are correlated.⁴ This noteworthy characteristic of FAP makes it as an applicable target in order to identifying and diagnosis as well as treatment of various sorts of malignancies including cancers.⁵ Since the first FAPI radiopharmaceutical was introduced in 2018 varieties of clinical trials have been accomplished which approved the high potential with more accuracy of radiolabeled FAPIs in comparison to fluorine-18 (¹⁸F)-fludeoxyglucose (FDG) for diagnostic purposes.^6,7 It turned out of the all mentioned radiolabeled FAPI derivatives, FAPI-02 and FAPI-04 represented the most promising characterizations for clinical indications including fast accumulation at FAP-positive tumors and rapid clearance from the body, resulting in very fast internalization into tumor sites and comparable tumor-to-organ ratios.⁸ All in all it is concluded that clinical utilities of FAPI-04 particularly as theranostics is so much better than its precursor (FAPI-02), since FAPI-04 has higher effective tumor uptake compared to the latter.⁹ The next considerable point can be mentioned about FAPIs’ capability to make radiolabeled compounds with variety of radionuclides. Different derivatives of FAPIs can be coupled through 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC), 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA), hydrazinonicotinic acid (HYNIC) to make radiolabeled compounds with different species of radionuclides including ¹⁸F, Technetium-99m (^99mTc), Gallium-68 (⁶⁸Ga), yttrium-90 (⁹⁰Y), Lutetium-177 (¹⁷⁷Lu), actinium-225 (²²⁵Ac), indium-111 (¹¹¹In).¹⁰

FAP-targeting platforms possess a remarkable potential for achieving broad acceptance in the field of medicine.^11-13 The latest advancements in FAPI positron emission tomography/computed tomography (PET/CT) indicate a wide array of potential uses in both cancer and non-oncological indications. Although investigations into various non-oncological applications are still in their early stages, accumulating evidence highlighting the FAPI PET outperforms [¹⁸F]-FDG PET in several cancer types, particularly in tumors where [¹⁸F]-FDG PET has shown to be either insensitive or nonspecific. This includes cancers of the liver, stomach, pancreas, lungs, colon, breast, and ovaries, where the increased sensitivity of FAPI compared to [¹⁸F]-FDG PET is clear. Despite FAPI PET consistently showing greater sensitivity than FDG in numerous cancers, it is important to note that FAPI has its limitations due to its accumulation in cases of benign fibrosis and inflammation. Now, there are some gaps in understanding the performance of PET scan by FAPI. One such gap involves how effectively the radiotracer can distinguish between benign and cancerous lesions, given its affinity for both. Distinguishing inflammatory lesions from tumor remains a significant challenge that requires more investigation. There is some optimism in the finding that different time-point scans conducted over several hours can reveal a clearance of activity in inflammation, while activity increases or plateaus in cancer; however, some degree of overlap between the two conditions is unavoidable. Furthermore, it is necessary to consider the correlation between histopathological and clinical findings to avoid misdiagnosis.¹³ Comprehensive immunological assessments of FAP overexpression in various infectious or inflammatory diseases may provide clarity on this matter. It is now evident that FAPI uptake may differ among distinct histological subtypes, especially in conditions with low FDG avidity. Various studies indicated that tumors with recognized low FDG avidity, like signet-ring gastric carcinoma or lung adenocarcinoma, gain the most advantages from employing FAPI PET.¹⁴ More extensive clinical investigations categorized by FDG uptake and histologic subtype are necessary to accurately define the role of FAPI PET.^15,16

A remaining knowledge gap is how much FAPI-PET uptake indicates prognostic evidence and if it can serve as a substitute for disease consequences. Numerous studies explored the prognostic significance of FAPI PET, revealing that the intensity of the FAP signal is related to disease extent clinical and severity, which in certain instances can predict disease outcomes; nonetheless, further research is necessary. The outlook for FAPI PET is very encouraging. Nonetheless, we must also take into account alternative radionuclidic types of FAPI imaging such as SPECT imaging by ^99mTc-labeled FAPI, which, despite having lower resolution, will be more adaptable and economical, and potentially more advantageous in settings with limited PET scanner availability.¹⁷ On the opposite end of the cost spectrum, FAPI PET/magnetic resonance imaging (MRI) could also enhance flexibility in clinical decisions, since MRI is considered the standard imaging technique for various cancers such as soft tissue sarcomas, breast, brain or liver cancer.¹⁸

In conclusion, properly executed clinical trials involving adequately large patient cohorts to permit reliable subgroup analysis, thorough examination of histological subtypes, and the relationship with long-term clinical outcomes will be crucial in shaping the future of FAPI PET. Recent advancements in ultra-sensitive PET imaging technology will undoubtedly enhance the effectiveness of FAPI imaging. Eventually, the ability to focus on FAP expression through either FAP-targeted platforms or radiotracer treatment creates extra possibilities for image-guided therapy in the future years. FAPI-derived radiopharmaceuticals will significantly contribute to improving human health care worldwide. FAPI’s trajectory suggests a paradigm shift in precision oncology, but larger trials and innovative imaging protocols are needed to realize its potential fully.

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability Statement

Data sharing not applicable to this article.

Declaration of AI Use in Scientific Writing

The authors declare that they have not used AI tools or technologies to prepare this paper.

Ethical Approval

Not applicable.

References

1. Puré E, Blomberg R. Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene 2018; 37:4343-57. doi: 10.1038/s41388-018-0275-3 [Crossref] [ Google Scholar]
2. Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov 2019; 18:99-115. doi: 10.1038/s41573-018-0004-1 [Crossref] [ Google Scholar]
3. Rezaei S, Gharapapagh E, Dabiri S, Heidari P, Aghanejad A. Theranostics in targeting fibroblast activation protein bearing cells: progress and challenges. Life Sci 2023; 329:121970. doi: 10.1016/j.lfs.2023.121970 [Crossref] [ Google Scholar]
4. Scott AM, Cebon J. Clinical promise of tumour immunology. Lancet 1997; 349:Sii19-22. doi: 10.1016/s0140-6736(97)90016-7 [Crossref] [ Google Scholar]
5. Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W. 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med 2019; 60:801-5. doi: 10.2967/jnumed.119.227967 [Crossref] [ Google Scholar]
6. Pang Y, Zhao L, Luo Z, Hao B, Wu H, Lin Q. Comparison of 68Ga-FAPI and 18F-FDG uptake in gastric, duodenal, and colorectal cancers. Radiology 2021; 298:393-402. doi: 10.1148/radiol.2020203275 [Crossref] [ Google Scholar]
7. Elboga U, Sahin E, Kus T, Cayirli YB, Aktas G, Uzun E. Superiority of 68Ga-FAPI PET/CT scan in detecting additional lesions compared to 18FDG PET/CT scan in breast cancer. Ann Nucl Med 2021; 35:1321-31. doi: 10.1007/s12149-021-01672-x [Crossref] [ Google Scholar]
8. Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med 2018; 59:1415-22. doi: 10.2967/jnumed.118.210443 [Crossref] [ Google Scholar]
9. Primac I, Tabury K, Tasdogan A, Baatout S, Herrmann K. The molecular blueprint of targeted radionuclide therapy. Nat Rev Clin Oncol 2025; 22:869-94. doi: 10.1038/s41571-025-01069-z [Crossref] [ Google Scholar]
10. Zhao L, Chen J, Pang Y, Fu K, Shang Q, Wu H. Fibroblast activation protein-based theranostics in cancer research: a state-of-the-art review. Theranostics 2022; 12:1557-69. doi: 10.7150/thno.69475 [Crossref] [ Google Scholar]
11. Abbasi Marjani A, Nader ND, Aghanejad A. Exosomes as targeted diagnostic biomarkers: recent studies and trends. Life Sci 2024; 354:122985. doi: 10.1016/j.lfs.2024.122985 [Crossref] [ Google Scholar]
12. Mojahedi M, Tohidkia MR, Kheyrolahzadeh K, Aghanejad A. Theranostics exosomes as autophagy mediators in cancer: recent trends and advances. Eur J Pharmacol 2025; 1002:177823. doi: 10.1016/j.ejphar.2025.177823 [Crossref] [ Google Scholar]
13. Kheyrolahzadeh K, Mojahedi M, Tohidkia MR, Aghanejad A. Theranostic antibody conjugates: a review of recent trends and applications in cancer. Bioorg Chem 2025; 164:108915. doi: 10.1016/j.bioorg.2025.108915 [Crossref] [ Google Scholar]
14. Chen H, Pang Y, Li J, Kang F, Xu W, Meng T. Comparison of [68Ga]Ga-FAPI and [18F]FDG uptake in patients with gastric signet-ring-cell carcinoma: a multicenter retrospective study. Eur Radiol 2023; 33:1329-41. doi: 10.1007/s00330-022-09084-9 [Crossref] [ Google Scholar]
15. Wu Y, Wang X, Sun X, Gao X, Zhang S, Shen J. Fibroblast activation protein targeting radiopharmaceuticals: from drug design to clinical translation. Acta Pharm Sin B 2025; 15:4511-42. doi: 10.1016/j.apsb.2025.07.009 [Crossref] [ Google Scholar]
16. Lee EJ, Chung HW, So Y, Kim IA, Kim HJ, Lee KY. Recent advances in PET and radioligand therapy for lung cancer: FDG and FAP. Cancers (Basel) 2025; 17:2549. doi: 10.3390/cancers17152549 [Crossref] [ Google Scholar]
17. Mori Y, Haberkorn U, Giesel FL. 68Ga- or 18F-FAPI PET/CT-what it can and cannot. Eur Radiol 2023; 33:7877-8. doi: 10.1007/s00330-023-09715-9 [Crossref] [ Google Scholar]
18. Sun L, Hao P, Peng R. Comparison of 68Ga-FAPI PET CT/MRI and 18F-FDG PET/CT in metastatic lesions of gynecological cancers: a systematic review and head-to-head meta-analysis. Acta Radiol 2025; 66:174-83. doi: 10.1177/02841851241297836 [Crossref] [ Google Scholar]