Targeting DNA Damage and Repair Machinery via Delivering WEE1 Inhibitor and Platinum (IV) Prodrugs to Stimulate STING Pathway for Maximizing Chemo‐Immunotherapy in Bladder Cancer

Author:

Wang Wenkuan12,Yang Feiya12,Zhang Lingpu3,Wang Mingshuai12,Yin Lu12,Dong Xiying12,Xiao Haihua34,Xing Nianzeng125ORCID

Affiliation:

1. Department of Urology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China

2. State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China

3. Beijing National Laboratory for Molecular Sciences Laboratory of Polymer Physics and Chemistry Institute of Chemistry Chinese Academy of Sciences Beijing 100190 China

4. University of Chinese Academy of Sciences Beijing 100049 China

5. Department of Urology Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University Shanxi 030013 China

Abstract

AbstractBoth cisplatin‐based chemotherapy and immune checkpoint blockers (ICBs)‐based immunotherapy are the first‐line treatments for patients with advanced bladder cancer. Cancer cells can develop resistance to cisplatin through extensive DNA repair, while a low response rate to ICBs is mostly due to the presence of an immunosuppressive microenvironment and low PD‐L1 expression. Herein, a glutathione (GSH)‐responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) is designed. NP2 can be triggered by GSH in cancer cells, and the released MK1775 can inhibit the activity of WEE1 protein, which ultimately increases DNA damage by cisplatin. Genome‐wide RNA sequencing first reveals that NP2 can inhibit DNA repair machinery by interfering with the cell cycle and significantly activate the stimulator of interferon genes pathway. Tumor growth is significantly inhibited by NP2 in vivo. As innate and adaptive immune responses are stimulated, the immunosuppressive microenvironment is modified, and the “immune cold tumor” is transformed into an “immune hot tumor". In addition, NP2 can upregulate PD‐L1 expression in tumor cells, thereby increasing the response rate of PD‐L1 monoclonal antibody (αPD‐L1) and eliciting long‐term immune responses in both primary and metastatic tumors.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Capital Health Research and Development of Special Fund

Publisher

Wiley

Subject

Mechanical Engineering,Mechanics of Materials,General Materials Science

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