Abstract
Abstract
CD44, a multifunctional transmembrane glycoprotein, is not only a bystander but also a crucial driver of cancer progression that promotes cancer stem cell maintenance, metastasis, and resistance to therapy. Therefore, CD44 is recognized as a promising therapeutic target in advanced malignancies. Here, we discuss its unique features, such as its structural diversity, which arise from alternative splicing and the post-translational modifications of cleavage and phosphorylation. In addition, we discuss the function of CD44 as a multivalent cell adhesion receptor for extracellular matrix components, including hyaluronic acid, fibronectin, osteopontin, and TSG6, thereby regulating lymphocyte activation, cell–cell interactions, cell adhesion, and migration within the extracellular matrix. Moreover, the emerging role of CD44 as a co-receptor of receptor tyrosine kinases such as epidermal growth factor receptor, c-MET, and vascular endothelial growth factor receptor 2 is highlighted to elucidate the contribution of CD44 to malignant signaling networks. We also discuss its potential as a therapeutic target in advanced cancers, particularly its applications in unconjugated antibodies, antibody–drug conjugates, peptide-based inhibitors, and chimeric antigen receptor-T cell therapies. We conclude by addressing the limitations observed in clinical studies and outlining promising opportunities for future development.