Fibroblast activation protein alpha (FAP) (FAP)

Fibroblast activation protein alpha (FAP) is a type II transmembrane serine protease belonging to the prolyl oligopeptidase family [UniProt]. It is uniquely characterized by its dual enzymatic activity, functioning as both a dipeptidyl peptidase and an endopeptidase capable of cleaving Pro-Xaa bonds [PubMed: 25100345]. While FAP expression is nearly undetectable in most healthy adult tissues, it is highly upregulated in the cancer-associated fibroblasts (CAFs) of more than 90% of epithelial tumors, as well as in sites of active tissue remodeling such as fibrosis and chronic inflammation [NCBI Gene]. This restricted expression pattern makes FAP an attractive therapeutic target and diagnostic biomarker for various solid malignancies [PubMed: 30233458]. In the tumor microenvironment, FAP promotes tumor growth, invasion, and immunosuppression by remodeling the extracellular matrix and modulating signaling molecules [PubMed: 29434305]. Current therapeutic strategies include FAP-targeted radiopharmaceuticals for imaging and therapy, FAP-activated prodrugs designed to release cytotoxic payloads specifically within the tumor stroma, and FAP-directed immunotherapies like CAR-T cells [ClinicalTrials.gov]. Its role in non-malignant conditions like liver fibrosis and rheumatoid arthritis also suggests potential applications beyond oncology [PubMed: 25100345].

Other names

Prolyl endopeptidase FAPSepraseFAPalpha170 kDa melanoma membrane-bound gelatinaseDipeptidyl peptidase FAPSurface-expressed protease

Mechanisms include the inhibition of FAP's enzymatic protease activity, antibody-dependent cellular cytotoxicity (ADCC) directed at cancer-associated fibroblasts, targeted delivery of radionuclides for imaging and radiotherapy (radiotheranostics), site-specific cleavage of FAP-activated prodrugs to release cytotoxic payloads, and recruitment of T-cells via CAR-T cells or bispecific antibodies [PubMed: 30233458, ClinicalTrials.gov].