Dipeptidyl peptidase-4 (DPP4), also known as cluster of differentiation 26 (CD26), is a multifunctional type II transmembrane glycoprotein with enzymatic and non-enzymatic roles in metabolism, immune regulation, tissue remodeling, and cancer. DPP4/CD26 is widely expressed on epithelial, endothelial, stromal, and immune cells and exists both as a membrane-bound protein and a soluble circulating form, enabling broad systemic effects (1–3). Through its proteolytic activity, DPP4/CD26 cleaves incretin hormones, chemokines, neuropeptides, and cytokines, thereby regulating glucose homeostasis, immune cell trafficking, and inflammatory signaling (3,4). Accordingly, DPP4 inhibitors are widely used in the treatment of type 2 diabetes mellitus (5). Beyond its metabolic function, accumulating evidence implicates DPP4 in the pathogenesis of cardiovascular disease, organ fibrosis, and infectious diseases (2,3,4). DPP4 also plays a complex and context-dependent role in cancer biology. Its expression is dysregulated across multiple malignancies, where it may function as either a tumor-promoting or tumor-suppressive factor depending on cellular and microenvironmental context (6). In colorectal cancer, DPP4 marks a subpopulation of cancer stem cells with high metastatic potential. Notably, experimental evidence demonstrates that anti-DPP4 antibody therapy suppresses epithelial-mesenchymal transition and metastasis (7).
