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

Overview

Journal Adv Healthc Mater

Specialties Biomedical Engineering
Biotechnology

Date 2024 Oct 13

PMID 39396375

Authors

Yihao Zhu

Yajian Li

Xuwen Li

Yuan Yu

Lingpu Zhang

Hanchen Zhang

Can Chen

Dong Chen

Mingshuai Wang

Nianzeng Xing

Feiya Yang

Wahafu Wasilijiang

Xiongjun Ye

Affiliations

Soon will be listed here.

Abstract

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)-mPEG, P-APm) encapsulating both a HIF-2α 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.

Citing Articles

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

Zhu Y, Li Y, Li X, Yu Y, Zhang L, Zhang H Adv Healthc Mater. 2024; 13(32):e2402973.

PMID: 39396375 PMC: 11670269. DOI: 10.1002/adhm.202402973.

References

Choueiri T, Bauer T, Papadopoulos K, Plimack E, Merchan J, Mcdermott D . Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021; 27(5):802-805. PMC: 9128828. DOI: 10.1038/s41591-021-01324-7. View

Mcdermott D, Lee J, Bjarnason G, Larkin J, Gafanov R, Kochenderfer M . Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021; 39(9):1020-1028. PMC: 8078336. DOI: 10.1200/JCO.20.02363. View

Mu Y, Maharjan Y, Dutta R, Kim H, Wei X, Kim J . Dimethyloxaloylglycine induces pexophagy in a HIF-2α dependent manner involving autophagy receptor p62. Biochem Biophys Res Commun. 2020; . DOI: 10.1016/j.bbrc.2020.02.051. View

Scharping N, Rivadeneira D, Menk A, Vignali P, Ford B, Rittenhouse N . Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021; 22(2):205-215. PMC: 7971090. DOI: 10.1038/s41590-020-00834-9. View

Bukavina L, Bensalah K, Bray F, Carlo M, Challacombe B, Karam J . Epidemiology of Renal Cell Carcinoma: 2022 Update. Eur Urol. 2022; 82(5):529-542. DOI: 10.1016/j.eururo.2022.08.019. View

Deeks E . Belzutifan: First Approval. Drugs. 2021; 81(16):1921-1927. DOI: 10.1007/s40265-021-01606-x. View

Liu Y, Xu D, Liu Y, Zheng X, Zang J, Ye W . Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy. Biomaterials. 2022; 284:121516. DOI: 10.1016/j.biomaterials.2022.121516. View

McDonald P, Chafe S, Brown W, Saberi S, Swayampakula M, Venkateswaran G . Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. Gastroenterology. 2019; 157(3):823-837. DOI: 10.1053/j.gastro.2019.05.004. View

Yuan P, Cao W, Zang Q, Li G, Guo X, Fan J . The HIF-2α-MALAT1-miR-216b axis regulates multi-drug resistance of hepatocellular carcinoma cells via modulating autophagy. Biochem Biophys Res Commun. 2016; 478(3):1067-73. DOI: 10.1016/j.bbrc.2016.08.065. View

10.

Zhu Y, Li Y, Li X, Yu Y, Zhang L, Zhang H . Targeting Hypoxia and Autophagy Inhibition via Delivering Sonodynamic Nanoparticles With HIF-2α Inhibitor for Enhancing Immunotherapy in Renal Cell Carcinoma. Adv Healthc Mater. 2024; 13(32):e2402973. PMC: 11670269. DOI: 10.1002/adhm.202402973. View

11.

Mao C, Jin W, Xiang Y, Zhu Y, Wu J, Liu X . Realizing Highly Efficient Sonodynamic Bactericidal Capability through the Phonon-Electron Coupling Effect Using Two-Dimensional Catalytic Planar Defects. Adv Mater. 2022; 35(9):e2208681. DOI: 10.1002/adma.202208681. View

12.

Jin D, Zhu Y, Liu M, Yu W, Yu J, Zheng X . A Leaking-Proof Theranostic Nanoplatform for Tumor-Targeted and Dual-Modality Imaging-Guided Photodynamic Therapy. BME Front. 2023; 4:0015. PMC: 10085250. DOI: 10.34133/bmef.0015. View

13.

Davis L, Recktenwald M, Hutt E, Fuller S, Briggs M, Goel A . Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy. Cancers (Basel). 2022; 14(5). PMC: 8909461. DOI: 10.3390/cancers14051259. View

14.

Falcomata C, Barthel S, Schneider G, Rad R, Schmidt-Supprian M, Saur D . Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer. Cancer Discov. 2023; 13(2):278-297. PMC: 9900325. DOI: 10.1158/2159-8290.CD-22-0876. View

15.

Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z . Immunogenic cell death in cancer therapy: Present and emerging inducers. J Cell Mol Med. 2019; 23(8):4854-4865. PMC: 6653385. DOI: 10.1111/jcmm.14356. View

16.

Mei L, Chen X, Wei F, Huang X, Liu L, Yao J . Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria. Autophagy. 2023; 19(11):2997-3013. PMC: 10549199. DOI: 10.1080/15548627.2023.2234797. View

17.

Han L, Huang R, Liu S, Huang S, Jiang C . Peptide-conjugated PAMAM for targeted doxorubicin delivery to transferrin receptor overexpressed tumors. Mol Pharm. 2010; 7(6):2156-65. DOI: 10.1021/mp100185f. View

18.

Yang K, Yue L, Yu G, Rao L, Tian R, Wei J . A hypoxia responsive nanoassembly for tumor specific oxygenation and enhanced sonodynamic therapy. Biomaterials. 2021; 275:120822. DOI: 10.1016/j.biomaterials.2021.120822. View

19.

You L, Wang X, Wu W, Nepovimova E, Wu Q, Kuca K . HIF-1α inhibits T-2 toxin-mediated "immune evasion" process by negatively regulating PD-1/PD-L1. Toxicology. 2022; 480:153324. DOI: 10.1016/j.tox.2022.153324. View

20.

Peng Y, Xiong L, Zhou Z, Ning K, Li Z, Wu Z . Single-cell transcriptomics reveals a low CD8 T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma. J Immunother Cancer. 2022; 10(2). PMC: 8819783. DOI: 10.1136/jitc-2021-004206. View