Fap

Overview

Fibroblast activation protein (FAP), also designated FAP-α, is a type II transmembrane serine protease and dipeptidyl peptidase belonging to the prolyl oligopeptidase family. It is encoded by the FAP gene and functions both as a cell-surface endopeptidase and a dipeptidyl peptidase, cleaving substrates at post-proline peptide bonds. Under normal physiological conditions, FAP expression is negligible in healthy adult tissue; however, it is robustly upregulated in activated stromal fibroblasts during tissue remodeling, wound healing, and pathological fibrogenesis. Its expression is characteristically high in cancer-associated fibroblasts (CAFs) within the tumor microenvironment, as well as in activated hepatic stellate cells (HSCs) during liver fibrosis, making it a clinically significant marker of reactive stromal biology.

The biological significance of FAP extends beyond its catalytic activity. As a surface protein selectively overexpressed at disease sites—including solid tumors, fibrotic organs, and chronically inflamed tissues—FAP has emerged as a high-value theranostic target. Its restricted expression in pathological stroma, combined with low baseline presence in healthy tissue, offers a favorable therapeutic window for targeted drug delivery, radiolabeled imaging, and immune cell engineering strategies. FAP-expressing cells actively remodel the extracellular matrix, modulate immune infiltration, and sustain pro-tumorigenic and pro-fibrotic microenvironments, placing FAP at a mechanistic crossroads between structural remodeling and immune suppression.

Focus of Latest Publications

Recent publications have continued to position fibroblast activation protein (FAP) as a key target in fibrotic disease, tumor imaging, and radiopharmaceutical therapy. In metabolic dysfunction-associated steatotic liver disease, FAP was investigated as a serine protease upregulated in liver and blood in chronic liver disease, with proposed pro-fibrotic activity and potential effects on circulating substrates such as fibroblast growth factor 21 and α2-antiplasmin. In liver fibrosis, activated hepatic stellate cells were highlighted as a major FAP-expressing population, and a CD163 antibody-conjugated lipid nanoparticle system was used to deliver FAP-specific CAR macrophage mRNA in situ, reducing extracellular matrix accumulation and promoting fibrosis resolution in a mouse model.

Several studies focused on FAP-targeted therapeutic strategies in fibrotic and inflammatory settings. CAR exosomes derived from FAP-targeting CAR T cells were shown to inhibit intrauterine fibrosis, support endometrial regeneration, and increase pregnancy rates in a mouse model of intrauterine adhesion, while avoiding the cytokine-release toxicity associated with FAP-targeted T cells. In aging-related periodontitis, FAP upregulation in senescent gingival fibroblasts was linked to enhanced collagenase activity, osteoclast differentiation, and activation of nuclear factor kappa B signaling; pharmacologic inhibition of FAP reduced periodontal inflammation, suppressed osteoclast activity, and preserved alveolar bone. FAP was also explored as an early biomarker in chronic lung allograft dysfunction, reflecting continued interest in its role in fibrotic remodeling.

In oncology, FAP remained a prominent imaging and therapeutic target. Multiple studies developed and evaluated FAP-targeted PET tracers, including [18F]AlF-AA-FAPT, [68Ga]Ga-TRAP-(FAPI)3, and PEG-modified dimeric FAP radiotracers, each designed to improve tumor uptake, retention, and target-to-background contrast relative to earlier FAPI agents. Preclinical and pilot clinical data showed favorable pharmacokinetics and imaging performance, including improved visualization of primary and metastatic lesions in selected cancer types. A small-molecule drug conjugate, OncoFAP glidotin, was also tested in dogs with spontaneous FAP-positive tumors and produced responses in most treated animals with no severe treatment-related adverse events.

FAP-targeted radiopharmaceutical therapy has also advanced into early clinical evaluation. [177Lu]Lu-RTX-2358 was administered to patients with advanced FAP-expressing solid tumors, showing a manageable safety profile, measurable tumor absorbed doses, and disease stabilization in some cases. In oral squamous cell carcinoma, FAP-expressing cancer-associated fibroblasts were implicated in shaping an immunosuppressive microenvironment through WNT2-mediated reprogramming of C1QC+ macrophages, with FAP inhibition reducing this stromal-immune crosstalk and improving anti-PD-1 therapy efficacy. Together, these studies underscore FAP as a versatile target spanning fibrosis, immune modulation, and tumor diagnosis and treatment.

Key Publications

• Jun Fibroblast activation protein and down-stream effects on its substrates in metabolic dysfunction-associated steatotic liver disease. (Scandinavian journal of gastroenterology, 2026, PMID 42233208): "Fibroblast activation protein (FAP) is a serine protease upregulated in liver and blood in patients with chronic liver disease of several etiologies."
• May mRNA-laden LNP-enabled in situ CAR-macrophage alleviates liver fibrosis via inhibiting activated HSCs and modulating the immune microenvironment. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42213756): "Fibroblast activation protein (FAP), highly expressed by activated HSCs, is a pivotal player in the pathogenesis of liver fibrosis."
• May A Small-Molecule Drug Conjugate Targeting FAP Exhibits Potent Activity in Dogs with Spontaneous Tumors. (Journal of medicinal chemistry, 2026, PMID 42142054): "Here, we report the results of a proof-of-concept study in canine cancer patients with OncoFAP glidotin, a small molecule-based targeted cytotoxic directed against Fibroblast Activation Protein."
• May Development of CAR Exosomes Targeting FAP for the Treatment of Intrauterine Adhesion. (Journal of extracellular vesicles, 2026, PMID 42060824): "Together, these findings demonstrate that FAP is a critical target for fibrotic disease intervention and that CAR-T-derived EVs represent a safe and effective vesicle-based therapeutic modality."
• May Development and Pilot Clinical Study of a Novel FAP-Targeted PET Tracer for PET Imaging of Tumors. (Analytical chemistry, 2026, PMID 42062218): "In recent years, fibroblast activation protein (FAP) has become a promising target, with FAPI tracers proving effective for tumor diagnosis."
• Jun Inhibiting fibroblast activation protein mitigates aging-related periodontitis by blocking nuclear factor kappa B-mediated osteoclastogenesis. (International immunopharmacology, 2026, PMID 41966776): "This study investigates the role of fibroblast activation protein (FAP) in aging-related periodontitis and explores its therapeutic potential."
• Jun Chelator-guided radiosynthesis, preclinical evaluation, and clinical study of [68Ga]Ga-TRAP-(FAPI)3 for positron emission tomography imaging of tumors. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41946434): "Recently, radiolabeled inhibitors targeting fibroblast activation protein (FAP) in the tumor microenvironment have shown considerable promise for tumor radiotheranostics."
• Mar Rational design and preclinical evaluation of 68Ga-labeled PEG-modified dimeric FAP radiotracers. (Bioorganic chemistry, 2026, PMID 41887115): "Fibroblast activation protein (FAP), which is highly overexpressed on cancer-associated fibroblasts (CAFs) while being minimally expressed in normal adult tissues, has emerged as an attractive target for tumor imaging and radionuclide therapy."
• May FAP+ fibroblasts promote C1QC+ macrophage infiltration via WNT2 signaling to exacerbate T cell exhaustion in oral squamous cell carcinoma. (Cancer letters, 2026, PMID 41831519): "Here, we identified fibroblast activation protein (FAP)-expressing CAFs as the key orchestrators of immunosuppression through WNT2-mediated reprogramming of C1QC+ macrophages."
• May Initial Clinical Experience with [177Lu]Lu-RTX-2358 Radiopharmaceutical Therapy Targeting Fibroblast Activation Protein: Biodistribution, Pharmacokinetics, and Dosimetry. (Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2026, PMID 41786480): "This series of case studies provides the first clinical experience with the fibroblast activation protein-α (FAP)-targeting radiopharmaceutical [177Lu]Lu-RTX-2358 in patients with advanced solid tumors."