选择性雌激素受体降解剂（SERD）的发展，为ER阳性晚期乳腺癌的临床治疗带来了新的思路。联合疗法的成功应用，激发了对其他目标的探索，以预防乳腺癌的进展。硫氧还蛋白还原酶（TrxR）是一种可以调节细胞氧化还原平衡的重要酶，被认为是一种潜在的抗癌治疗靶点。在这项研究中，我们首次组合临床SERD候选药物--G1T48（NCT03455270），与TrxR抑制剂--N-杂环卡宾金（I）[NHC-Au(I)]，形成双重靶向复合物，可以调节两个信号通路。最有效的复合物23通过降解ER并抑制TrxR活性，展现出显著的抗增殖特性。有趣的是，它能通过ROS诱导免疫原性细胞死亡（ICD）。这是阐明ER/TrxR-ROS-ICD轴在ER阳性乳腺癌中的作用的首个证据，这项研究可能激发新的具有新机制的药物开发。体内异种移植研究表明，复合物23对小鼠模型中的MCF-7细胞具有优异的抗增殖活性。 Copyright © 2023。Elsevier Ltd. 发布。

The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.Copyright © 2023. Published by Elsevier Ltd.