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An ER-Targeting Iridium(III) Complex which Induces Immunogenic Cell Death in Non-Small Cell Lung Cancer

Last updated :2020-12-11

Source: School of Chemistry
Edited by: Tan Rongyu, Wang Dongmei

Recently Prof. Hui Chao’s group from the School of Chemistry at Sun Yat-sen University presented a cyclometalated iridium(III) complex (Ir1) that can induce immunogenic cell death (ICD) in non-small cell lung cancer (NSCLC). The complex’s immunotherapeutic properties are demonstrated in lung cancer cells both in vitro and in vivo. To the best of our knowledge, this Ir(III) complex is the first iridium(III) complex to induce ICD in non-small cell lung cancer.

 
Fig.1. Schematic representation of Ir1-induced immunogenic cell death.

NSCLC accounts for about 85% of lung cancer. Most patients with advanced NSCLC are still treated with conventional chemotherapy regimens, such as platinum drugs. And drug resistance almost always occurs. Inducing ICD is considered to be a promising strategy for cancer immunotherapy. Chemotherapeutic drug-induced ICD can be used as a novel treatment modality for NSCLC. While breaking the drug resistance barrier, it can stimulate a tumor-specific T cell immune response and enhance the anti-tumor effects of immunotherapy. ICD inducers for NSCLC are therefore in great demand. However, to date, recent studies have shown that only a few chemotherapeutic drugs induce ICD, and even fewer metal drugs can induce ICD as a single drug. Indeed, the majority of current research is confined to platinum(IV) complexes, ruthenium(II) complexes or copper(II) complexes. The ability of Ir(III) complexes have not been found to cause ICD.

Ir1 selectively targets the ER and causes severe intracellular damage by triggering the production of ER stress and ROS, as well as mitochondrial membrane potential (MMP) loss. Strikingly, Ir1 shows high cytotoxicity and induces multiple characteristics of ICD (i.e. surface exposure of CRT, extracellular release of HMGB1 and ATP), in A549 lung cancer cells as well as the cisplatin (CDDP) resistant strain A549R cells. The results of vaccination experiment demonstrate the successful ICD induction of Ir1 in an immunocompetent homogene mouse model. After treatment, Ir1 elicited antitumor CD8+ T cell responses. Therefore, Ir1 is an excellent candidate as an antitumor agent with the dual-action of ICD and chemotherapy for NSCLC.

Recently this research data was published as a Very Important Paper in Angewandte Chemie International Edition. The paper is entitled "An ER-Targeting Iridium(III) Complex which Induces Immunogenic Cell Death in Non-Small Cell Lung Cancer". Prof. Hui Chao is the corresponding author, and Ph.D. candidate Lili Wang is the first author. 

This work was supported by the National Science Foundation of China (Nos. 21525105, 21778079, and 21907112), the Ministry of Education of China (No. IRT-17R111) and the Fundamental Research Funds for the Central Universities (No. 20lgjc01).

Link to the paper: https://doi.org/10.1002/anie.202013987