Fap, or Fibroblast Activation Protein, is a membrane-bound protease with both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. It is highly expressed in cancer-associated fibroblasts (CAFs) within the tumor microenvironment of many solid cancers, while having limited expression in normal adult tissues. Fap can modulate the tumor microenvironment by remodeling the extracellular matrix (ECM), and its overexpression on CAFs is associated with poor prognosis in various cancers. Due to its restricted expression pattern and dual enzymatic activities, Fap has emerged as a unique therapeutic target [3,4,5].

In preclinical studies, radiolabeled FAP-2286, a FAP-binding peptide coupled to a radionuclide chelator, demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. Biodistribution studies in mice showed rapid and persistent uptake of 68Ga-FAP-2286, 111In-FAP-2286, and 177Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. 177Lu-FAP-2286 also exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts [1]. Additionally, compared to the standard tumor tracer [18F]FDG, FAP-targeted tracers show better tumor-to-background ratios (TBR) in many cancer indications, and unlike [18F]FDG, they do not require dietary restrictions on the part of the patient [2].

In conclusion, Fap is a significant biomarker in the tumor microenvironment, highly relevant for cancer diagnosis and therapy. Preclinical in vivo studies, such as those using radiolabeled FAP-2286 in mouse models, have shown promise for Fap-targeted radionuclide imaging and therapy, highlighting its potential in improving the treatment of FAP-positive tumors [1].