Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside

Digestive system cancers, including malignancies of the oral cavity, esophagus, stomach, liver, pancreas, and colorectum, rank among the most prevalent tumors worldwide, with persistently high incidence and mortality. Notch signaling is a highly conserved pathway that orchestrates essential cellular processes such as differentiation, proliferation, and development; its dysregulation has been increasingly linked to various diseases, particularly digestive system cancers. Accumulating evidence indicates that aberrant Notch signaling is closely associated with the development of these malignancies, where it influences tumor initiation, progression, metastasis, and therapy resistance. Notably, depending on cellular context, Notch signaling may also exhibit tumor-suppressive effects in certain digestive system cancers. Understanding the role of Notch signaling in these tumors is essential for the development of more effective therapeutic strategies. Currently, multiple preclinical studies are investigating agents targeting the Notch pathway. This review summarizes current evidence on Notch signaling in digestive system cancers and points to open questions that warrant further study to inform future therapeutic strategies.