Delta-like protein 4–Notch receptor interaction (DLL4–Notch)

The Delta-like protein 4 (DLL4)–Notch receptor interaction is a fundamental signaling mechanism that regulates vascular development and maintains tissue homeostasis [1, 8]. DLL4 is a transmembrane ligand that, upon binding to Notch receptors (primarily Notch1 and Notch4) on neighboring cells, triggers proteolytic cleavage and the release of the Notch intracellular domain (NICD) to modulate gene expression [12, 16]. In the tumor microenvironment, DLL4 is typically upregulated by vascular endothelial growth factor (VEGF) and acts as a negative regulator of angiogenic sprouting to ensure the formation of a stable, functional vascular network [2, 4]. Therapeutic strategies targeting this interaction, such as monoclonal antibodies or bispecific agents, aim to disrupt this regulatory balance, leading to non-productive angiogenesis characterized by excessive but non-functional vessel growth [3, 5]. This chaotic vasculature fails to provide adequate blood supply, resulting in tumor hypoxia and growth inhibition, even in cases resistant to traditional anti-VEGF therapies [6, 7]. Beyond its role in cancer, the DLL4–Notch axis is involved in immune cell modulation, particularly macrophage polarization, and has been investigated as a target for cardiovascular and inflammatory diseases [14, 16].

Other names

Delta-like ligand 4DLL4Delta-4hdelta2AOS6Notch signaling pathway

Inhibition of the interaction between the Delta-like ligand 4 (DLL4) and Notch receptors (primarily Notch1 and Notch4) to disrupt the regulation of angiogenic sprouting. This blockade leads to excessive, non-functional vessel formation (hypersprouting), which results in poor tumor perfusion, increased hypoxia, and subsequent inhibition of tumor growth [1, 2, 4].