Notch signaling in the tumor microenvironment: recent advances and targeted therapeutics

The Notch signaling pathway, an evolutionarily conserved mechanism governing cell-cell communication, plays a pivotal and multifaceted role in shaping the tumor microenvironment (TME). This review provides a comprehensive overview of the core components and signaling mechanisms of the Notch pathway, encompassing both canonical and non-canonical signaling cascades. It further examines the dual functionality of Notch in tumorigenesis, functioning as either an oncogene or a tumor suppressor. A central focus of this review is the detailed investigation of the molecular mechanisms through which Notch signaling modulates key cellular constituents of the TME. Recent advances are systematically summarized, with emphasis on the role of Notch in regulating immune cell differentiation and function, angiogenesis, modulating cancer-associated fibroblasts, and maintenance of cancer stem cells. To facilitate clinical translation, the review highlights emerging therapeutic strategies targeting the Notch pathway, including γ-secretase inhibitors and modulators, monoclonal antibodies against ligands and receptors, small molecule inhibitors, and combination therapies integrating immune checkpoint inhibitors, chimeric antigen receptor immune cell therapy, cancer vaccines, and oncolytic viruses. Collectively, this work offers a systematic synthesis of recent progress in understanding the diverse roles of Notch signaling within the TME, emphasizing the therapeutic potential of modulating Notch signaling to reprogram the TME and enhance anti-tumor immunity.