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.

中文翻译：

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内皮ZEB1的失活阻碍了肿瘤的发展并使肿瘤对常规疗法敏感。

当前的抗血管生成疗法受到其细胞抑制特性，向肿瘤的药物输送少和副作用的限制。为了解决这些局限性，我们揭示了肿瘤进展期间肿瘤内皮富集的锌指转录因子ZEB1的作用。我们发现，在肺癌内皮细胞中具有高ZEB1表达的肺腺癌患者转移后的患病率增加，并且在诊断出肺癌后明显降低了总生存率。荷瘤小鼠中内皮ZEB1的缺失减少了肿瘤的血管生成，同时通过表观遗传抑制TGF-β信号传导引起持久的肿瘤血管正常化。因此，这导致改善的血液和氧气灌注，增强的化学疗法递送和免疫效应细胞浸润，以及减少的肿瘤生长和转移。此外，靶向血管ZEB1显着增强了无毒小剂量顺铂的抗癌活性。用小剂量抗程序性细胞死亡蛋白1（抗PD-1）抗体治疗可导致肿瘤消退并显着延长ZEB1缺失小鼠的生存期，从而赋予长期保护性抗癌免疫力。总的来说，我们证明了灭活内皮ZEB1可能为癌症治疗提供其他机会，且副作用最小。靶向内皮衍生的ZEB1并结合常规化学疗法或免疫检查点封锁疗法可产生有效且优越的抗癌作用。用小剂量抗程序性细胞死亡蛋白1（抗PD-1）抗体治疗可导致肿瘤消退并显着延长ZEB1缺失小鼠的生存期，从而赋予长期保护性抗癌免疫力。总的来说，我们证明了灭活内皮ZEB1可能为癌症治疗提供其他机会，且副作用最小。靶向内皮衍生的ZEB1并结合常规化学疗法或免疫检查点封锁疗法可产生有效且优越的抗癌作用。用小剂量抗程序性细胞死亡蛋白1（抗PD-1）抗体治疗可导致肿瘤消退并显着延长ZEB1缺失小鼠的生存期，从而赋予长期保护性抗癌免疫力。总的来说，我们证明了灭活内皮ZEB1可能为癌症治疗提供最小的副作用的替代机会。靶向内皮衍生的ZEB1并结合常规化学疗法或免疫检查点封锁疗法可产生有效且优越的抗癌作用。