Emerging roles of Notch signaling in the tumor microenvironment of digestive system cancers.

The Notch signaling pathway is an evolutionarily conserved cell-cell communication cascade with central roles in the development and progression of digestive system cancers. Beyond its established functions in tumor-cell proliferation and stemness, growing evidence indicates that Notch signaling also remodels the tumor microenvironment (TME). This review synthesizes the multifaceted roles of Notch signaling in the TME of digestive system malignancies. We discuss how aberrant Notch activity regulates the recruitment, polarization, and function of key tumor-infiltrating immune cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs), and dendritic cells (DCs), thereby fostering an immunosuppressive milieu. Notch signaling also drives the activation and sustained pro-tumorigenic activity of cancer-associated fibroblasts, promotes tumor angiogenesis, and contributes to extracellular matrix remodeling. Together, these effects establish a TME that supports digestive system cancer progression and therapy resistance. Given its central role in TME regulation, the Notch pathway represents a promising therapeutic target. We summarize current strategies, including Notch inhibitors and their combinations with immunotherapies, angiogenesis inhibitors, and other targeted therapies, that aim to overcome treatment resistance and improve clinical outcomes. A clearer understanding of Notch signaling in the TME will be essential for translating these insights into more effective therapies and improving prognosis in patients with digestive system cancers.