纳米医学介导的铜死亡在乳腺癌治疗中的应用和进展

doi:10.11904/j.issn.1002-3070.2025.02.010

摘要/Abstract

摘要： 近10年来,乳腺癌的新发病例和死亡病例均居女性恶性肿瘤首位,且发病率呈上升及年轻化趋势。乳腺癌表现出高度的异质性特征,容易对综合治疗方案产生耐药性。铜死亡作为一种由铜介导的新发现的调节性细胞死亡形式,与乳腺癌的发生发展密切相关。随着纳米医学的进步,以铜为代表的金属药物可通过纳米材料的特异性递送系统定向输送铜离子至肿瘤部位。这些金属药物通过诱导过量铜负荷、调节肿瘤微环境以及增强抗肿瘤免疫应答杀伤肿瘤细胞。因此,在乳腺癌治疗中,铜基纳米药物展现出显著的应用潜力。本文对铜死亡在乳腺癌发生发展中的作用机制及目前纳米医学介导的铜死亡在乳腺癌治疗中的应用及进展进行综述。

关键词: 铜死亡, 乳腺癌, 纳米医学, 铜基纳米药物, 耐药

Abstract: Over the past decade,the new cases and deaths of breast cancer has rank first among malignant tumors in women,and its incidence is rising,with a younger age trend.Breast cancer demonstrates a high degree of heterogeneity and is prone to drug resistance to comprehensive treatment.As a newly discovered regulatory cell death form mediated by copper,cuproptosis is closely related to the occurrence and development of breast cancer.With the advancement of nano-medicine,metal-based drugs represented by copper can selectively deliver copper ions to tumor sites through the specific delivery system of nanomaterials.These metal drugs kill tumor cells by inducing copper overload,regulating the tumor microenvironment,and enhancing anti-tumor immune response.Therefore,copper-based drugs exhibit significant application potential in the treatment of breast cancer.This article reviews of the mechanism of cuproptosis in the occurrence and development of breast cancer and the application and progress of nanomedicine-mediated cuproptosis in the treatment of breast cancer.

Key words: Cuproptosis, Breast cancer, Nano-medicine, Copper-based nano-medicine, Drug resistance

中图分类号:

R737.9

王锐, 马得原, 贾王强, 关泉林. 纳米医学介导的铜死亡在乳腺癌治疗中的应用和进展[J]. 实用肿瘤学杂志, 2025, 39(2): 144-150.

WANG Rui, MA Deyuan, JIA Wangqiang, GUAN Quanlin. Application and progress of nano-medicine mediated cuproptosis in the breast cancer treatment[J]. Journal of Practical Oncology, 2025, 39(2): 144-150.

参考文献

1 Bray F,Laversanne M,Sung H,et al.Global cancer statistics 2022:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA cancer J Clin,2024,74(3):229-263.
2 Li M,Wang H,Qu N,et al.Breast cancer screening and early diagnosis in China:a systematic review and meta-analysis on 10.72 million women[J].BMC Womens Health,2024,24(1):97.
3 Han B,Zheng R,Zeng H,et al.Cancer incidence and mortality in China,2022[J].J Natl Cancer Cent,2024,4(1):47-53.
4 Xia Z,Vermeulen S,Suwal U,et al.Cancer-associated fibroblasts mediate resistance to neoadjuvant therapy in breast cancer[J].Clin Transl Med,2024,14(7):e1779.
5 Liu X,Luo B,Wu X,et al.Cuproptosis and cuproptosis-related genes:emerging potential therapeutic targets in breast cancer[J].Biochim Biophys Acta Rev Cancer,2023,1878(6):189013.
6 Wang W,Mo W,Hang Z,et al.Cuproptosis:harnessing transition metal for cancer therapy[J].ACS Nano,2023,17(20):19581-19599.
7 Xue Q,Kang R,Klionsky DJ,et al.Copper metabolism in cell death and autophagy[J].Autophagy,2023,19(8):2175-2195.
8 Xie J,Yang Y,Gao Y,et al.Cuproptosis:mechanisms and links with cancers[J].Mol Cancer,2023,22(1):46.
9 Xing Z,Cui L,Feng Y,et al.Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments[J].Sci Rep,2024,14(1):16935.
10 Peng Y,Shi R,Yang S,et al.Cuproptosis-related gene DLAT is a biomarker of the prognosis and immune microenvironment of gastric cancer and affects the invasion and migration of cells[J].Cancer Med,2024,13(14):e70012.
11 Duan J,Zhang X,Xu J,et al.Unveiling a cuproptosis-related risk model and the role of FARSB in hepatocellular carcinoma[J].Heliyon,2024,10(12):e32289.
12 Wang N,Liu Y,Peng D,et al.Copper-based composites nanoparticles improve triple-negative breast cancer treatment with induction of apoptosis-cuproptosis and immune activation[J].Adv Healthc Mater,2024:e2401646.
13 Wang Y,Yin F,Jin Q,et al.Cuproptosis:mechanism and application in lymphoma[J].Curr Cancer Drug Targets,2024,14:1-14.
14 Wo＇zniak-Budych MJ,Staszak K,Staszak M.Copper and copper-based nanoparticles in medicine-perspectives and challenges[J].Molecules,2023,28(18):6687.
15 Song Y,Tan KB,Zhou SF,et al.Biocompatible copper-based nanocomposites for combined cancer therapy[J].ACS Biomater Sci Eng,2024,10(6):3673-3692.
16 Kang X,Wang J,Huang CH,et al.Diethyldithiocarbamate copper nanoparticle overcomes resistance in cancer therapy without inhibiting P-glycoprotein[J].Nanomedicine,2023,47:102620.
17 Sathiyavimal S,F Durán-Lara E,Vasantharaj S,et al.Green synthesis of copper oxide nanoparticles using abutilon indicum leaves extract and their evaluation of antibacterial,anticancer in human A549 lung and MDA-MB-231 breast cancer cells[J].Food Chem Toxicol,2022,168:113330.
18 Tsvetkov P,Coy S,Petrova B,et al.Copper induces cell death by targeting lipoylated TCA cycle proteins[J].Science,2022,375(6586):1254-1261.
19 Ge EJ,Bush AI,Casini A,et al.Connecting copper and cancer:from transition metal signaling to metalloplasia[J].Nat Rev Cancer,2022,22(2):102-113.
20 Yang S,Song Y,Hu Y,et al.Multifaceted roles of copper Ions in anticancer nanomedicine[J].Adv Healthc Mater,2023,12(23):e2300410.
21 Xia Q,Shen J,Wang Q,et al.Cuproptosis-associated ncRNAs predict breast cancer subtypes[J].PLoS One,2024,19(2):e0299138.
22 Li Z,Zhang H,Wang X,et al.Identification of cuproptosis-related subtypes,characterization of tumor microenvironment infiltration,and development of a prognosis model in breast cancer[J].Front Immunol,2022,13:996836.
23 Zhang G,Wang N,Ma S,et al.Comprehensive analysis of the effects of the cuprotosis-associated gene SLC31A1 on patient prognosis and tumor microenvironment in human cancer[J].Transl Cancer Res,2024,13(2):714-737.
24 Jiang ZR,Yang LH,Jin LZ,et al.Identification of novel cuproptosis-related lncRNA signatures to predict the prognosis and immune microenvironment of breast cancer patients[J].Front Oncol,2022,12:988680.
25 Yu H,Liu Y,Zhang W,et al.A signature of cuproptosis-related lncRNAs predicts prognosis and provides basis for future anti-tumor drug development in breast cancer[J].Transl Cancer Res,2023,12(6):1392-1410.
26 Pan Y,Zhang Q,Zhang H,et al.Prognostic and immune microenvironment analysis of cuproptosis-related lncRNAs in breast cancer[J].Funct Integr Genomics,2023,23(1):38.
27 Liu S,Huang J,Zhao W.Prognosis prediction and immune microenvironment features of breast cancer indicated by a cuproptosis-associated long non-coding RNA signature[J].Genes Dis,2024,11(5):101110.
28 Ning S,Lyu M,Zhu D,et al.Type-I AIE photosensitizer loaded biomimetic system boosting cuproptosis to Inhibit breast cancer metastasis and rechallenge[J].ACS Nano,2023,17(11):10206-10217.
29 Li Y,Liu J,Weichselbaum RR,et al.Mitochondria-targeted multifunctional nanoparticles combine cuproptosis and programmed cell death-1 downregulation for cancer immunotherapy[J].Adv Sci(Weinh),2024:e2403520.
30 Lu S,Li Y,Yu Y.Glutathione-scavenging celastrol-Cu nanoparticles induce self-amplified cuproptosis for augmented cancer immunotherapy[J].Adv Mater,2024,36(35):e2404971.
31 Liu T,Zhou Z,Zhang M,et al.Cuproptosis-immunotherapy using PD-1 overexpressing T cell membrane-coated nanosheets efficiently treats tumor[J].J Control Release,2023,362:502-512.
32 Lu Y,Fan X,Pan Q,et al.A mitochondria-targeted anticancer copper dithiocarbamate amplifies immunogenic cuproptosis and macrophage polarization[J].J Mater Chem B,2024,12(8):2006-2014.
33 Kong R,Sun G.Targeting copper metabolism:a promising strategy for cancer treatment[J].Front Pharmacol,2023,14:1203447.
34 Xu X,Ding C,Zhong H,et al.Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer[J].Front Immunol,2023,14:1165101.
35 Zhong X,Dai X,Wang Y,et al.Copper-based nanomaterials for cancer theranostics[J].Wiley Interdiscip Rev Nanomed Nanobiotechnol,2022,14(4):e1797.
36 Wu W,Pu Y,Shi J.Nanomedicine-enabled chemotherapy-based synergetic cancer treatments[J].J Nanobiotechnology,2022,20(1):4.
37 Zhang C,Huang T,Li L.Targeting cuproptosis for cancer therapy:mechanistic insights and clinical perspectives[J].J Hematol Oncol,2024,17(1):68.
38 Shang T,Yu X,Han S,et al.Nanomedicine-based tumor photothermal therapy synergized immunotherapy[J].Biomater Sci,2020,8(19):5241-5259.
39 Liu Z,Ling J,Wang N,et al.Redox homeostasis disruptors enhanced cuproptosis effect for synergistic photothermal/chemodynamic therapy[J].J Colloid Interface Sci,2024,678(Pt A):1060-1074.
40 Dai Y,Zhu L,Li X,et al.A biomimetic cuproptosis amplifier for targeted NIR-II fluorescence/photoacoustic imaging-guided synergistic NIR-II photothermal immunotherapy[J].Biomaterials,2024,305:122455.
41 Wu L,Lin H,Cao X,et al.Bioorthogonal Cu single-atom nanozyme for synergistic nanocatalytic therapy,photothermal therapy,cuproptosis and immunotherapy[J].Angew Chem Int Ed Engl,2024,63(27):e202405937.
42 Lu S,Tian H,Li B,et al.An ellagic acid coordinated copper-based nanoplatform for efficiently overcoming cancer chemoresistance by cuproptosis and synergistic inhibition of cancer cell stemness[J].Small,2024,20(17):e2309215.
43 Chen M,Xu C,Wang C,et al.Three birds with one stone:copper Ions assisted synergistic cuproptosis/chemodynamic/photothermal therapy by a three-pronged approach[J].Adv Healthc Mater,2024:e2401567.
44 Yang Z,Zhao Z,Cheng H,et al.In-situ fabrication of novel Au nanoclusters-Cu(2+)@sodium alginate/hyaluronic acid nanohybrid gels for cuproptosis enhanced photothermal/photodynamic/chemodynamic therapy via tumor microenvironment regulation[J].J Colloid Interface Sci,2023,641:215-228.
45 Wang YY,Zhang XY,Li SL,et al.AuPt-loaded Cu-doped polydopamine nanocomposites with multienzyme-mimic activities for dual-modal imaging-guided and cuproptosis-enhanced photothermal/nanocatalytic therapy[J].Anal Chem,2023,95(37):14025-14035.
46 Sang D,Wang K,Sun X,et al.NIR-driven intracellular photocatalytic O(2)evolution on Z-Scheme Ni(3)S(2)/Cu(1.8)S@HA for hypoxic tumor therapy[J].ACS Appl Mater Interfaces,2021,13(8):9604-9619.
47 Ni C,Ouyang Z,Li G,et al.A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy[J].Acta Biomater,2023,164:474-486.
48 Li Y,Liu J,Chen Y,et al.Nanoparticles synergize ferroptosis and cuproptosis to potentiate cancer immunotherapy[J].Adv Sci(Weinh),2024,11(23):e2310309.
49 Sha R,Dong X,Yan S,et al.Cuproptosis-related genes predict prognosis and trastuzumab therapeutic response in HER2-positive breast cancer[J].Sci Rep,2024,14(1):2908.
50 Zhang D,Lu W,Zhuo Z,et al.Comprehensive analysis of a cuproptosis-related ceRNA network implicates a potential endocrine therapy resistance mechanism in ER-positive breast cancer[J].BMC Med Genomics,2023,16(1):96.
51 Wang Q,Huang CH,Wibowo FS,et al.Elesclomol-copper nanoparticles overcome multidrug resistance in cancer cells[J].ACS Appl Mater Interfaces,2024,16(11):13509-13524.
52 Xu Y,Liu SY,Zeng L,et al.An enzyme-engineered nonporous copper(I)coordination polymer nanoplatform for cuproptosis-based synergistic cancer therapy[J].Adv Mater,2022,34(43):e2204733.
53 Jia W,Tian H,Jiang J,et al.Brain-targeted HFn-Cu-REGO nanoplatform for site-specific delivery and manipulation of autophagy and cuproptosis in glioblastoma[J].Small,2023,19(2):e2205354.
54 Xia J,Hu C,Ji Y,et al.Copper-loaded nanoheterojunction enables superb orthotopic osteosarcoma therapy via oxidative stress and cell cuproptosis[J].ACS Nano,2023,17(21):21134-21152.
55 Jin XK,Liang JL,Zhang SM,et al.Orchestrated copper-based nanoreactor for remodeling tumor microenvironment to amplify cuproptosis-mediated anti-tumor immunity in colorectal cancer[J].Materials Today,2023,68:108-124.
56 Yan C,Lv H,Feng Y,et al.Inhalable nanoparticles with enhanced cuproptosis and cGAS-STING activation for synergistic lung metastasis immunotherapy[J].Acta Pharm Sin B,2024,14(8):3697-3710.
57 Wan Y,Chen J,Li J,et al.Cu0-based nanoparticles boost anti-tumor efficacy via synergy of cuproptosis and ferroptosis enhanced by cuproptosis-induced glutathione synthesis disorder[J].Colloids Surf B Biointerfaces,2024,245:114196.

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