Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.

中文翻译：

---

修饰的 C 型利钠肽使肿瘤脉管系统正常化，重振抗肿瘤免疫力，并改善实体瘤治疗


肿瘤微环境（TME）中氧气和营养物质的缺乏会引发异常的血管生成，从而产生功能失调和渗漏的血管，从而无法充分灌注肿瘤组织。由此产生的缺氧、代谢紊乱加剧以及免疫抑制性 TME 的产生破坏了抗癌疗法的功效。建议使用精心安排的血管生成抑制剂来克服这些问题并使 TME 正常化。在这里，我们提出了一种使用 C 型利钠肽 (dCNP) 衍生物的替代性基于激动剂的标准化方法。在接受 dCNP 治疗的小鼠中，肿瘤组织中的多个基因表达特征受到影响。在几种小鼠原位和皮下实体瘤模型（包括结肠腺癌和胰腺癌）中，这种耐受性良好的药物刺激了高功能肿瘤血管的形成，以减少缺氧。 dCNP 的施用还抑制基质发生和细胞外基质的重塑，并降低肿瘤间质液压力。此外，dCNP 治疗可重振抗肿瘤免疫反应。给予 dCNP 可减缓原发性小鼠肿瘤的生长并抑制其转移。此外，将 dCNP 纳入化疗、放疗或免疫治疗方案中可提高其对抗免疫功能正常小鼠实体瘤的功效。这些结果证明了使用脉管系统正常化激动剂改善实体瘤治疗的原理证明，并将 dCNP 描述为同类药物中的首创。