Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Int J Biol Sci. 2023 Feb 27;19(5):1490-1508. doi: 10.7150/ijbs.78248. eCollection 2023.
IFNγ has long been recognised as a key mediator of tumour immunity and angiostasis. However, IFNγ modulation for cancer therapy is still unsuccessful due to its complex effects on various host cells. In this study, we found that treatment of Lewis lung carcinoma transplants with cisplatin often caused IFNγ-dependent tumour vascular damage. IFNγ induced endothelial glycolysis and lactate production, leading to enhanced endocytosis of vascular endothelial (VE)-cadherin and vessel leakage. We have also developed anti-IFNγ nanoparticles coated with a clot-binding peptide CREKA (CREKA-lipo-anti-IFNγ), which targets the fibrin-fibronectin complex that appears in the leaky site of damaged tumour blood vessels. Blocking IFNγ activity in the leakage site of capillaries using nanoparticles rescued VE-cadherin distribution on the endothelial cellular surface, promoted blood vessel integrity, and improved drug delivery. In conclusion, IFNγ blockade in capillary leak site protected tumour blood vessels from lactate-dependent VE-cadherin loss and enhanced drug delivery during chemotherapy, which provides a basis for tissue-specific IFNγ blockade for tumour therapy.
IFNγ 长期以来被认为是肿瘤免疫和血管生成的关键介质。然而，由于 IFNγ 对各种宿主细胞的复杂影响，其用于癌症治疗的效果仍然不理想。在这项研究中，我们发现顺铂治疗 Lewis 肺癌移植瘤常导致 IFNγ 依赖性肿瘤血管损伤。IFNγ 诱导内皮细胞糖酵解和乳酸生成，导致血管内皮（VE）-钙黏蛋白的内吞作用增强和血管渗漏。我们还开发了一种包被有纤维蛋白结合肽 CREKA（CREKA-脂-抗 IFNγ）的抗 IFNγ 纳米颗粒，该纳米颗粒靶向出现在受损肿瘤血管渗漏部位的纤维蛋白-纤维连接蛋白复合物。使用纳米颗粒在毛细血管渗漏部位阻断 IFNγ 活性，挽救 VE-钙黏蛋白在血管内皮细胞表面的分布，促进血管完整性，并改善药物递送。总之，在毛细血管渗漏部位阻断 IFNγ 可防止肿瘤血管因乳酸依赖性 VE-钙黏蛋白丢失，并增强化疗期间的药物递送，为肿瘤治疗的组织特异性 IFNγ 阻断提供了依据。
