DLL4 (Delta-like ligand 4) is a key ligand in the Notch signaling pathway, a conserved system regulating cell fate, angiogenesis, and tissue development. Expressed primarily on endothelial cells and certain tumor cells, DLL4 binds to Notch receptors (Notch1/Notch4) on adjacent cells, triggering proteolytic cleavage and release of the Notch intracellular domain (NICD). This activates downstream genes (e.g., Hes/HeY) critical for vascular remodeling and tip-stalk cell specification during angiogenesis.
In cancer, DLL4-mediated Notch signaling promotes tumor angiogenesis by orchestrating vessel sprouting and maturation. However, excessive DLL4 inhibition paradoxically disrupts functional vasculature, leading to hypoxic tumor environments. DLL4 antibodies (e.g., Enoticumab, Demcizumab) were developed to block DLL4-Notch interactions, aiming to suppress tumor growth by destabilizing blood supply. Preclinical studies showed efficacy in solid tumors, but clinical trials revealed mixed outcomes, with challenges like compensatory VEGF upregulation and dose-limiting toxicities (e.g., vascular leaks, hypertension).
Research continues to explore combination therapies (e.g., with VEGF inhibitors or chemotherapy) and biomarker-driven approaches to optimize DLL4-targeted treatments. Despite hurdles, DLL4 remains a compelling target due to its unique role in pathological angiogenesis and tumor-stroma crosstalk.