Posttranslational modifications in regulating Notch signaling pathway and tumor angiogenesis: from molecular mechanisms to therapeutic applications

Tumorigenesis exhibits complex interactions with the vascular system. Targeting angiogenesis represents an emerging strategy for remodeling the tumor microenvironment. The Notch signaling pathway, a key regulatory mechanism, orchestrates tumor angiogenesis by modulating endothelial cell differentiation and vascular homeostasis. However, the clinical translation of Notch-targeted therapies is limited by severe toxicities due to lack of tissue specificity. Posttranslational modifications (PTMs) chemically regulate protein functions, thereby influencing multiple signaling cascades including Notch signaling. Notably, Notch-associated PTMs are essential for signal transduction integrity. Some types in PTMs, such as glycosylation and ubiquitination, are the core for maintaining the integrity of the Notch signaling pathway. Dysfunctional Notch-related PTMs disrupt signal fidelity and drive pathological angiogenesis. This review systematically explores: (i) crosstalk between Notch signaling and tumor angiogenesis, (ii) regulatory roles of PTMs on Notch molecules in tumor angiogenesis, and (iii) therapeutic potential of targeting Notch-related PTMs for anti-angiogenic strategies in tumor. We aim to elucidate the molecular nexus of PTMs-Notch-angiogenesis in tumor progression. Furthermore, we discuss therapeutic challenges in modulating Notch signaling pathway-dependent PTMs within tumor angiogenesis, focusing on critical barriers to their clinical translation in oncology.