DLL4 (Delta-like canonical Notch ligand 4) is a Notch pathway ligand that activates NOTCH1 and NOTCH4 receptors 1. In vascular biology, DLL4 negatively regulates endothelial cell proliferation, migration, and angiogenic sprouting 2. DLL4 plays critical roles in multiple disease contexts: in diabetic vasculopathy, DLL4 and NOTCH3 are key drivers of basement membrane thickening and microvascular dysfunction 3; in sepsis-induced acute lung injury, DLL4+ neutrophils activate Notch1-mediated PANoptosis in endothelial cells, exacerbating lung injury 4; and in atherosclerosis, macrophage DLL4 signaling induces vascular smooth muscle cell senescence, promoting plaque vulnerability in type 2 diabetes 5. In cancer, DLL4 expression promotes tumor stemness and therapy resistance—in HER2+ breast cancer, DLL4+ tumor cells resist chemotherapy while soluble DLL4 activates Notch signaling in neutrophils to induce neutrophil extracellular trap formation, excluding lymphocytes and enhancing immune escape 6. DLL4 and NOTCH3 overexpression correlate with advanced breast cancer stage, high grade, and poor prognosis 7. Clinically, DLL4-targeted CAR-T cell therapy shows promise for sensitizing resistant breast cancers 6, while DLL4-Fc fusion proteins support T lymphoid progenitor generation for immune reconstitution 8.