Molecular advancements in targeting fibroblast activation protein (FAP) in cancer therapies.

Abstract

INTRODUCTION Fibroblast activation protein (FAP) is a membrane-bound serine protease highly expressed by activated stromal cells in the majority of epithelial-derived malignancies, on the contrary FAP expression is limited in normal adult tissues. Beyond the recognizing role as a marker of cancer-associated fibroblasts (CAFs), accumulating evidence indicates that FAP actively contributes to extracellular matrix remodeling, immune suppression, tumor progression and therapeutic resistance, making it an attractive target for both cancer diagnosis and treatment. AREAS COVERED We summarize current knowledge regarding the molecular organization, enzymatic functions and regulatory mechanisms governing the expression of FAP as well as its role within the tumor microenvironment. We further discuss recent advances in FAP-directed strategies, encompassing molecular imaging and theranostics, antibody-based agents, enzyme-activated prodrugs, CAR-engineered immune cells, vaccines, nanocarriers and extracellular vesicle-based delivery systems. EXPERT OPINION FAP has emerged as one of the most promising stromal biomarkers in precision oncology. Nevertheless, CAF heterogeneity and context-dependent biological functions. Future efforts integrating spatial multiomics, radiomics and artificial intelligence are expected to refine patient stratification and facilitate the clinical implementation of FAP-targeted theranostic and immunomodulatory approaches.