文献类型：期刊文献

英文题名：Copper-Doped Polydopamine Nanoparticles-Mediated GSH/GPX4-Depleted Ferroptosis and Cuproptosis Sensitizes Lung Tumor to Checkpoint Blockade Immunotherapy

作者：Jiang, Cong[1];Li, Xianglong[2,3];Wan, Shiyue[1];Ji, Shuyu[1];Wang, Qinghua[2];Hu, Shiqi[4];Chen, Pengcheng[5];Wang, Bo[6];Ge, Tao[1];Zhang, Jing[1];Cao, Yuanyuan[2];Yang, Yang[1];Zhang, Dapeng[2];Li, Yongsheng[2,7];Zhang, Peng[1]

机构：[1]Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai 200092, Peoples R China;[2]East China Univ Sci & Technol, Frontier Sci Ctr Mat Biol & Dynam Chem, Shanghai Engn Res Ctr Hierarch Nanomat, Sch Mat Sci & Engn,Minist Educ,Lab Low Dimens Mat, Shanghai 200237, Peoples R China;[3]Jiangxi Sci & Technol Normal Univ, Inst Organ Chem, Jiangxi Prov Key Lab Organ Funct Mol, Nanchang 330013, Peoples R China;[4]Wenzhou Med Univ, Affiliated Hosp 1, Wenzhou 325015, Peoples R China;[5]Chinese Acad Sci, Shanghai Inst Immun & Infect, Shanghai 200031, Peoples R China;[6]Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Dept Clin Lab, Shanghai 201900, Peoples R China;[7]Shihezi Univ, Sch Chem & Chem Engn, State Key Lab Incubat Base Green Proc Chem Engn, Shihezi 832003, Peoples R China

年份：2025

卷号：21

期号：23

外文期刊名：SMALL

收录：;EI(收录号：20251618247531);WOS:【SCI-EXPANDED(收录号:WOS:001466861500001)】；

基金：C.J., X.L., S.W., and S.J. contributed equally to this work. This work was financially supported by the National Key Research and Development Program of China (Grant No. 2022YFC2403203), the National Natural Science Foundation of China (No. 81972172, 51621002, 22305081, 51972112, 52402344 and 32100716), Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX03), Basic Research Program of Shanghai (21JC1406003 and 19JC1411700), Leading Talents in Shanghai in 2018, Shanghai Sailing Program (23YF1408600), the 111 Project (B14018), Clinical Research Plan of SHDC (No. SHDC2020CR2020B), China Postdoctoral Science Foundation (No. 2021M703323), Funding of Shanghai Pulmonary Hospital (No. FKCX1904 and No. FKLY20004), Jiangxi Natural Provincial Science Foundation (No. 20242BAB20098) and Eaglet Program of Shanghai Pulmonary Hospital (Fkcy2301). All experiments on animals were operated in terms of the protocols approved by the Laboratory Animal Management Committee of East China University of Science and Technology (license number: ECUST-2020-04001).

语种：英文

外文关键词：cuproptosis; ferroptosis; glutathione response; hybrid nanoparticles; immune checkpoint immunotherapy

摘要：Immune checkpoint blockade (ICB) therapy offers hope for improved outcomes in lung cancer treatment, but its effectiveness is restricted by the presence of an immunosuppressive tumor microenvironment (TME), resulting in a limited response rate (< 20%). Here this study reports a tumor-site glutathione (GSH)/glutathione peroxidase (GPX4) dual-depletion strategy to induce tumor ferroptosis and amplify cuproptosis via a GSH-responsive polydopamine-based hybrid nanoparticle (termed CACuPDA). This approach triggers cellular lysis to reverse immunosuppressive TME and further enhance the therapeutic efficacy of lung tumors combined with anti-PD-L1-based ICB therapy. The released cinnamaldehyde (CA) can stimulate reactive oxygen species production, while Cu2+ can directly deplete GSH and suppress GPX4. Interestingly, Cu2+ induces cuproptosis by downregulating ferredoxin (FDX1) expression, whereas reduced Cu+ can catalyze hydroxyl radicals (OH) generation from overexpressed H2O2 at the tumor site. The redox imbalance amplifies ferroptosis and cuproptosis in lung tumor cells, releasing substantial amounts of cellular contents into the immunosuppressive TME, as evidenced by an increased amount of cytotoxic T cells and a decreased amount of immunosuppressive Treg cells. In addition, in vivo experimental results revealed that CACuPDA enhanced the therapeutic effect of anti-PD-L1 by about fivefold for lung tumor treatment, providing a promising strategy to improve ICB therapy for lung tumors.