Selective Targeting of Tip Endothelial Cells as a Therapeutic Strategy for Tumor Angiogenesis

ABSTRACT Tip endothelial cells ( Tip EC), the leading edge of angiogenic sprouts, are essential for pathological neo‐vascularization but remain difficult to target due to the lack of specific druggable markers. Here, we identify Doppel as a selective and druggable regulator of endothelial tip cell function. Doppel expression enhances Tip EC selection, directional migration, and regulates tip‐stalk cell dynamics by spatially controlling VEGFR2/Dll4/Src pathway. Genetic ablation of PRND (Doppel) reduces tip cell formation without affecting the stalk cells ( Stalk ECs) number in tumors, indicating its selective role in Tip ECs. Importantly, depletion of Tip ECs using the first‐in‐class monoclonal antibodies against a highly conserved WQF‐motif of Doppel robustly decreased the growth of tumors by selectively downregulating VEGFR2+ Tip ECs but not Stalk ECs. These findings position Doppel as a tumor Tip EC‐specific, druggable target that may offer a new avenue to enhance and refine anti‐angiogenic therapies in cancer treatment.