Cyclometalated iridium(III) complex based on isoquinoline alkaloid synergistically elicits the ICD response and IDO inhibition via autophagydependent ferroptosis  

作　　者：Yuan Lu Shan-Shan Wang Meng-Ya Li Rong Liu Meng-Fan Zhu Liang-Mei Yang Feng-Yang Wang Ke-Bin Huang Hong Liang 

机构地区：[1]State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources,Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources(Ministry of Education of China),Collaborative Innovation Center for Guangxi Ethnic Medicine,School of Chemistry and Pharmaceutical Sciences,Guangxi Normal University,Guilin 541004,China [2]Department of Pharmacy,School of Medicine,Guangxi University of Science and Technology,Liuzhou 545005,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期424-437,共14页药学学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(22177022,22267005);the Natural Science Foundation of Guangxi Province of China(AD22035193).

摘　　要：The development of anticancer drugs to treat triple-negative breast cancer(TNBC)is an ongoing challenge.Immunogenic cell death(ICD)has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy.However,only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC.Therefore,new agents with potentially effective chemoimmunotherapeutic response are required.In this study,five new cyclometalated Ir(III)complexes containing isoquinoline alkaloid C^N ligands were designed and synthesized.Among them,Ir-1 exhibited the highest in vitro cytotoxicity.Mechanistically,Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase(IDO)inhibition via reactive oxygen species(ROS)-mediated endoplasmic reticulum(ER)stress in MDA-MB-231 cells.When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells,antitumor CD8^(+)T-cell response and Foxp3þT-cell depletion were induced,resulting in long-lasting antitumor immunity in TNBC cells.Moreover,combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects.Based on these results,Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

关 键 词：Organometallic complex Cyclometalated iridium complex Isoquinoline alkaloid ER stress Autophagy-dependent ferroptosis Immunogenic cell death IDO inhibition CHEMOIMMUNOTHERAPY 

分 类 号：R73[医药卫生—肿瘤]