Current antiangiogenic
therapy is limited by its
cytostatic property, scarce drug delivery to the
tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a
tumor endothelium-enriched zinc-finger
transcription factor, during
tumor progression. We discovered that the patients who had
lung adenocarcinomas with high ZEB1 expression in
tumor endothelium had increased prevalence of
metastases and markedly reduced overall survival after the diagnosis of
lung cancer. Endothelial ZEB1 deletion in
tumor-bearing mice diminished
tumor angiogenesis while eliciting persistent
tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and
oxygen perfusion, enhanced
chemotherapy delivery and immune effector cell infiltration, and reduced
tumor growth and
metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose
cisplatin. Treatment with low-dose anti-
programmed cell death protein 1 (anti-PD-1) antibody elicited
tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for
cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional
chemotherapy or
immune checkpoint blockade therapy may yield a potent and superior anticancer effect.