Notch signaling and cancer: Insights into chemoresistance, immune evasion, and immunotherapy

The Notch signaling pathway is a fundamental and highly conserved cell-to-cell communication system vital for embryonic development and tissue maintenance. However, its dysregulation has been associated with the initiation, progression, and chemoresistance of various cancers. In this comprehensive review, we will take an in-depth look at the multiple roles of the Notch family in cancer pathogenesis, immune response, and resistance to chemotherapy. We delve into the complicated mechanisms by which Notch signaling promotes tumor growth and development, including its influence on TME remodeling and immune evasion strategies. We will also be discussing recent studies that shed light on the connection between cancer stemness and chemoresistance mediated through the activation of Notch signaling pathways. Elucidation of the interplay between the Notch pathway and major constituents of the TME, including immune cells and cancer-associated fibroblasts, is necessary for the development of targeted therapies against Notch-driven tumors. We further discuss the potential of targeting Notch signaling alone or in combination with standard chemotherapy and immunotherapy as a potent strategy to overcome chemoresistance and improve patient outcomes. We conclude by discussing the challenges and future prospects of using Notch signaling as a therapeutic target in cancer treatment, focusing on how precision medicine and combination approaches are important.