TY - JOUR AU - Fu, Rong AU - Li, Yi AU - Jiang, Nan AU - Ren, Bo-Xue AU - Zang, Chen-Zi AU - Liu, Li-Juan AU - Lv, Wen-Cong AU - Li, Hong-Mei AU - Weiss, Stephen AU - Li, Zheng-Yu AU - Lu, Tao AU - Wu, Zhao-Qiu T1 - Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies PY - 2020/03/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI131507 VL - 130 IS - 3 UR - https://doi.org/10.1172/JCI131507 SP - 1252 EP - 1270 PB - The American Society for Clinical Investigation ER -