AUTHOR=Wang Shuang-Shuang , Lv Hui-Lin , Nie Rong-Zu , Liu Ya-Ping , Hou Yan-Jie , Chen Chen , Tao Xing-Yue , Luo Huo-Min , Li Pei-Feng 

TITLE=Notch signaling in cancer: metabolic reprogramming and therapeutic implications

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1656370

DOI=10.3389/fimmu.2025.1656370

ISSN=1664-3224

ABSTRACT=The evolutionarily conserved Notch signaling pathway is essential for cell-fate determination, organogenesis, and tissue homeostasis. Notch receptors and their ligands are transmembrane proteins with epidermal growth factor–like repeats; ligand–receptor binding triggers canonical Notch signaling. Notch signaling is context dependent in cancer, functioning as either an oncogene or a tumor suppressor. Aberrant Notch activation promotes epithelial–mesenchymal transition, sustains cancer stem–like phenotypes, and drives metabolic reprogramming, thereby facilitating tumor progression and therapeutic resistance. Current clinical efforts target the pathway with γ-secretase inhibitors (GSIs), monoclonal and bispecific antibodies, and synthetic Notch (synNotch) approaches. Clinical translation, however, is constrained by dose-limiting toxicity, a paucity of predictive biomarkers, and compensatory resistance through intersecting pathways. Priorities for future work include the development of highly selective Notch modulators, biomarker-guided combination regimens, and targeted delivery systems to realize the translational potential of Notch-targeted therapies in precision oncology.