Dipeptidyl peptidase-4 in the tumor microenvironment of the digestive system: Molecular mechanisms and therapeutic targets

Digestive system cancers represent nearly half of all global cancer cases and are associated with high mortality rates. Although immunotherapy has ushered in a new era for the treatment of digestive system cancers, the complexity and diversity of the immunosuppressive tumor microenvironment (TME) pose significant challenges to effective immunotherapy for digestive tumors. Dipeptidyl peptidase 4 (DPP4), also known as CD26, has garnered considerable attention for its role within the TME, where it plays a crucial role in the initiation and progression of digestive system cancers and serves as a predictive biomarker for certain cancers. Additionally, it is involved in regulating immune responses, angiogenesis, ferroptosis activation, tumor-associated inflammation, neurotransmission, and metastasis. Thus, DPP4 inhibitors play a pivotal role in modulating the intricate tumor ecosystem, contributing to the control of digestive system cancer development. Therefore, a deeper understanding of DPP4's mechanisms in the TME holds promise for establishing essential theoretical frameworks for developing novel treatment strategies for digestive system cancers. This review explores the regulatory role of DPP4 in the TME of digestive system cancers and its clinical implications, aiming to provide insights into potential advancements in oncological therapies.