德克萨斯大学甘波谊团队取得一项新突破。他们发现了铜死亡-免疫串扰启示克服免疫治疗耐药性的策略。2026年6月22日出版的《细胞》杂志发表了这项成果。

课题组人员发现CD8+ T细胞介导的抗肿瘤免疫增强了肿瘤细胞对铜倾的易感性，导致铜倾诱导剂在免疫正常宿主中比免疫缺陷宿主具有更强的肿瘤抑制作用。从机制上讲，铜原性肿瘤细胞作为免疫原性细胞死亡的一种形式，释放与损伤相关的分子模式，激活树突状细胞并增强抗肿瘤免疫。反过来，CD8+ T细胞源性干扰素(IFN)-γ通过激活信号换能器和转录激活子1 (STAT1)-IFN调节因子-1 （IRF1）信号轴，增强肿瘤细胞中FDX1的转录，从而提高肿瘤细胞对铜增生的敏感性。因此，在多个临床前模型中，铜体增生诱导剂与抗程序性细胞死亡配体1 （PD-L1）治疗相结合可以放大肿瘤铜体增生，并显示出克服PD-L1治疗耐药性的有效性。他们的发现揭示了一种以前未被认识到的抗肿瘤免疫和铜增生之间的联系，并强调了一种潜在的治疗方法，通过靶向这种独特的细胞死亡途径来对抗肿瘤免疫治疗耐药性。

据了解，铜沉积是最近发现的一种铜依赖性细胞死亡形式，依赖于铁氧还蛋白1 （FDX1）介导的蛋白脂酰化。

附：英文原文

Title: Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance

Author: Guang Lei, Zhengze Lu, Zhihao Xu, Chen Braun, David Huo, Jian Gao, Lin Tan, Ting Hong, Shengrong Wu, Mingchuang Sun, Xi Zhao, Qidong Li, Xiong Chen, Yuelong Yan, Hyemin Lee, Chao Mao, Li Zhuang, Li-Ting Ku, Nahum Puebla, Hampartsoum Barsoumian, Jun Yao, Lingzhi Hong, Jianjun Zhang, Hai Tran, Jiun-Kae Jack Lee, Don Gibbons, Ara Vaporciyan, John Heymach, Chunru Lin, Eyal Gottlieb, Mingjian James You, James W. Welsh, Steven H. Lin, Xingxing Zang, Ziyi Li, Boyi Gan

Issue&Volume: 2026-06-22

Abstract: Cuproptosis is a recently identified form of copper-dependent cell death that depends on ferredoxin 1 (FDX1)-mediated protein lipoylation. Here, we reveal that CD8+ T cell-mediated antitumor immunity enhances tumor cell susceptibility to cuproptosis, leading to a more potent tumor-suppressive effect of cuproptosis inducers in immunocompetent hosts compared with immunodeficient ones. Mechanistically, cuproptotic tumor cells act as a form of immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and enhance antitumor immunity. Reciprocally, CD8+ T cell-derived interferon (IFN)-γ enhances FDX1 transcription in tumor cells by activating the signal transducer and activator of transcription 1 (STAT1)-IFN regulatory factor-1 (IRF1) signaling axis, resulting in heightened tumor cell sensitivity to cuproptosis. Consequently, combining a cuproptosis inducer with anti-programmed cell death ligand 1 (PD-L1) therapy amplifies tumoral cuproptosis and demonstrates efficacy in overcoming PD-L1 therapy resistance across multiple preclinical models. Our findings unveil a previously unrecognized connection between antitumor immunity and cuproptosis and highlight a potential therapeutic approach to counteract tumor immunotherapy resistance by targeting this unique cell death pathway.

DOI: 10.1016/j.cell.2026.05.036

Source: https://www.cell.com/cell/abstract/S0092-8674(26)00636-7

期刊信息

Cell：《细胞》，创刊于1974年。隶属于细胞出版社，最新IF：66.85

官方网址：https://www.cell.com/

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