Targeting Hypoxia and Autophagy Inhibition via Delivering Sonodynamic Nanoparticles With HIF-2α Inhibitor for Enhancing Immunotherapy in Renal Cell Carcinoma

被引:0
|
作者
Zhu, Yihao [1 ]
Li, Yajian [1 ]
Li, Xuwen [1 ]
Yu, Yuan [2 ]
Zhang, Lingpu [3 ,4 ]
Zhang, Hanchen [3 ,4 ]
Chen, Can [5 ]
Chen, Dong [1 ]
Wang, Mingshuai [1 ]
Xing, Nianzeng [1 ]
Yang, Feiya [1 ]
Wasilijiang, Wahafu [1 ,6 ]
Ye, Xiongjun [1 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Natl Canc Ctr, Natl Clin Res Ctr Canc,Dept Urol, Beijing 100021, Peoples R China
[2] Chinese Acad Sci, Zhejiang Canc Hosp, Hangzhou Inst Med, Hangzhou 310022, Zhejiang, Peoples R China
[3] Chinese Acad Sci, Inst Chem, Beijing Natl Lab Mol Sci, Lab Polymer Phys & Chem, Beijing 100190, Peoples R China
[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
[5] Zunyi Med Univ, Affiliated Hosp 2, Dept Oncol, Zunyi 563000, Guizhou, Peoples R China
[6] Shanxi Med Univ, Chinese Acad Med Sci, Shanxi Prov Canc Hosp, Canc Hosp,Dept Urol,Shanxi Hosp, Taiyuan 030013, Shanxi, Peoples R China
基金
北京市自然科学基金; 中国国家自然科学基金;
关键词
HIF-2; alpha; immunotherapy; renal cell carcinoma; sonodynamic therapy; MICROENVIRONMENT; AXIS;
D O I
10.1002/adhm.202402973
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Immune checkpoint blockers (ICBs) therapy stands as the first-line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia-responsive polymer (Poly(4,4 '-azobisbenzenemethanol-PMDA)-mPEG5k, P-APm) encapsulating both a HIF-2 alpha inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from "immune-cold" to "immune-hot", thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC. This study reports on a hypoxia-responsive nanoparticle loaded with a HIF-2 alpha inhibitor (belzutifan), and the ultrasonic sensitizer (Chlorin e6, Ce6), which can inhibit tumor hypoxia and autophagy signaling pathways, and downregulate PD-L1 expression in tumor cells, leading to improved efficacy of alpha PD-1. Overall, it presents a promising strategy of targeted therapy combined with immunotherapy for treating renal cell carcinoma. image
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页数:18
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