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.