Endothelial deletion of the neddylation E2 enzyme UBE2M inhibits tumor growth by promoting nonproductive angiogenesis.

Neddylation is highly activated in many human cancers and may serve as a therapeutic target for clinical treatment. However, the role of neddylation in tumor angiogenesis remains unclear. Here, we demonstrate that the neddylation E2 enzyme UBE2M was upregulated in tip cells and was essential for tumor vascular sprouting. We showed that UBE2M-mediated neddylation of STAT1 enhanced its phosphorylation and promoted the transcription of DLL4. This elevated DLL4 expression in tip cells activated Notch signaling in adjacent stalk cells, thereby maintaining the tip-stalk cell balance and ensuring organized vascular patterning. Consequently, endothelial cell-specific deletion of UBE2M reduced DLL4 expression, leading to excessive but nonproductive sprouting due to uncontrolled tip cell formation and lack of stalk cell support, which ultimately suppressed tumor growth. Importantly, targeting endothelial neddylation potently sensitized various tumors to anti-VEGF therapy. Together, our findings unveil UBE2M as a key regulator of angiogenic signaling and identify it as a promising antiangiogenic target in cancer.