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Prof. Liu Zhaoqian’s Team Publishes a Research Article in Angew. Chem. Int. Ed Revealing the Restoration of the Immunogenicity of Tumor Cells via Copper Chaperone Inhibition

2022-06-12

Recently, Professor Liu Zhaoqian’s team from Institute of Clinical Pharmacology, Xiangya Hospital of Central South University, has published a research article titled “Restoration of the Immunogenicity of Tumor Cells for Enhanced Cancer Therapy via Nanoparticle-Mediated Copper Chaperone Inhibition” in Angew. Chem in Angew. Chem. Int. Ed (IF: 16.25). This article is the first to report an oxidation-responsive nanoparticle NP2, loaded with a tetravalent cisplatin prodrug (CisPt(IV)) and a copper chaperone inhibitor (DC_AC50) prodrug, which could enhance the chemotherapeutic effect and trigger an intense immune response.



Professor Liu Zhaoqian from Xiangya Hospital of Central South University, Professor Wang Jing from Peking University School of Pharmaceutical Sciences and Researcher Xiao Haihua from Institute of Chemistry, Chinese Academy of Sciences are the corresponding authors of this article. Ding Feixiang, graduate student from class of 2019 is the first author; Xiangya Hospital of Central South University is the first affiliation.


As an important transition metal element involved in many physiological processes, copper plays an important role in the occurrence and development of tumors, angiogenesis and metastasis. Previous studies on the functions of copper-related proteins or pathways in tumor therapy have shown that interfering with intratumor copper transportation in tumor cells can not only play an anti-tumor effect by disrupting the copper homeostasis in tumor cells, but also significantly enhance the chemotherapeutic effect by affecting the intracellular transportation of platinum-based drugs in tumor cells. Cisplatin is the first-line drug used in clinical treatment of various solid tumors. Unlike chemotherapy drugs such as oxaliplatin and mitoxantrone, which can induce immunogenic cell death (ICD) effect through endoplasmic reticulin (ER) stress, cisplatin is incapable of eliciting sufficiently intense ER stress, which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Therefore, through appropriate strategies to enhance the ER stress and ICD effect of cisplatin, conversion of tumor cells into vaccines can trigger anti-tumor immunogenicity, which may bring new breakthroughs in improving the therapeutic effect of cisplatin.


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This study found that the expression of copper chaperone protein Atox1 in the tumor of non-small cell lung cancer patients receiving cisplatin chemotherapy was significantly negatively correlated with its prognosis. The copper chaperone Atox1 inhibitor DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1-ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin.


Later, to further improve the delivery efficiency and synergistic effect of the two drugs, the team developed an reactive oxygen species (ROS)-sensitive nanoparticles NP2 loaded with a cisplatin(IV) prodrug (CisPt(IV)) and copper chaperone inhibitor DC_AC50. The experimental results showed that the nanoparticles not only achieved the chemo-sensitization effect, but also promote a remarkable accumulation of intracellular cisplatin and copper, thereby inducing significant ROS generation. Excessive ROS then elicits intense ER stress, which facilitates the immunogenic cell death (ICD), to restore immunogenicity of tumor cells, so as to effectively promote the maturation and antigen cross-presentation of dendritic cells, activate anti-tumor immunity, and promote the formation of immune memory. This study provides a new treatment thought for improving the platinum-based chemosensitivity of tumor cells and restoring the immunogenicity of tumor cells for enhanced immunochemotherapy.


Link to the Original Article: https://onlinelibrary.wiley.com/doi/10.1002/anie.202203546


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