Cuproptosis: A novel therapeutic target for non-small cell lung cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

DONG Dong , ZHANG Yajie ,  LI Hecheng

Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China;

Corresponding author：

LI Hecheng, Email: lihecheng2000@hotmail.com

Keywords：

Copper; cuproptosis; non-small cell lung cancer

DOI：

10.7507/1007-4848.202403060

Video：

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Abstract Full text Figures/Tables Video References Cited by

Cuproptosis, recently defined as a unique form of cell death distinct from programmed cell death, is triggered by copper overload within mitochondria. Genes associated with cuproptosis have been found to correlate with tumorigenesis and tumor progression, making the targeting of cuproptosis pathways a promising direction for anti-tumor therapies. Copper ion carriers can transport copper ions into cells, inducing cuproptosis and laying the foundation for its application in cancer treatment. This article elaborates on the homeostasis of copper and the mechanisms related to cuproptosis, further clarifying the relationship between cuproptosis and lung cancer treatment targets. This review aims to summarize current progress in research related to cuproptosis and lung cancer, providing new theories and bases for the clinical treatment of lung cancer.

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2.	Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-Mutated NSCLC. N Engl J Med, 2023, 389(2): 137-147.
3.	Hong L, Negrao MV, Dibaj SS, et al. Programmed death-ligand 1 heterogeneity and its impact on benefit from immune checkpoint inhibitors in NSCLC. J Thorac Oncol, 2020, 15(9): 1449-1459.
4.	Mok TSK, Wu YL, Kudaba L, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet, 2019, 393(10183): 1819-1830.
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6.	Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
7.	Cobine PA, Brady DC. Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death. Mol Cell, 2022, 82(10): 1786-1787.
8.	Porporato PE, Filigheddu N, Pedro JMB-S, et al. Mitochondrial metabolism and cancer. Cell Res, 2018, 28(3): 265-280.
9.	Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol, 2017, 24(9): 1161-1180.
10.	Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol, 2019, 15(7): 681-689.
11.	Buccarelli M, D'Alessandris QG, Matarrese P, et al. Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth. J Exp Clin Cancer Res, 2021, 40(1): 228.
12.	Raggi C, Taddei ML, Sacco E, et al. Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma. J Hepatol, 2021, 74(6): 1373-1385.
13.	Peng X, Zhu J, Liu S, et al. Signature construction and molecular subtype identification based on cuproptosis-related genes to predict the prognosis and immune activity of patients with hepatocellular carcinoma. Front Immunol, 2022, 13: 990790.
14.	Zhang Y, Chen K, Wang L, et al. Identification and validation of a prognostic signature of cuproptosis-related genes for esophageal squamous cell carcinoma. Aging (Albany NY), 2023, 15(17): 8993-9021.
15.	Luo L, Li A, Fu S, et al. [Cuproptosis-related immune gene signature predicts clinical benefits from anti-PD-1/PD-L1 therapy in non-small-cell lung cancer. Immunol Res, 2023, 71(2): 213-228.
16.	Tang Y, Wang T, Li Q, et al. A cuproptosis score model and prognostic score model can evaluate clinical characteristics and immune microenvironment in NSCLC. Cancer Cell Int, 2024, 24(1): 68.
17.	Ma C, Gu Z, Ding W, et al. Crosstalk between copper homeostasis and cuproptosis reveals a lncRNA signature to prognosis prediction, immunotherapy personalization, and agent selection for patients with lung adenocarcinoma. Aging (Albany NY), 2023, 15(22): 13504-13541.
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19.	Xu M, Mu J, Wang J, et al. Construction and validation of a cuproptosis-related lncRNA signature as a novel and robust prognostic model for colon adenocarcinoma. Front Oncol, 2022, 12: 961213.
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23.	Lutsenko S. Dynamic and cell-specific transport networks for intracellular copper ions. J Cell Sci, 2021, 134(21): jcs240523.
24.	Hernandez S, Tsuchiya Y, García-Ruiz JP, et al. ATP7B copper-regulated traffic and association with the tight junctions: copper excretion into the bile. Gastroenterology, 2008, 134(4): 1215-1223.
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27.	Pavithra V, Sathisha TG, Kasturi K, et al. Serum levels of metal ions in female patients with breast cancer. J Clin Diagn Res, 2015, 9(1): BC25-Bc27.
28.	Basu S, Singh MK, Singh TB, et al. Heavy and trace metals in carcinoma of the gallbladder. World J Surg, 2013, 37(11): 2641-2646.
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31.	Yu Z, Zhou R, Zhao Y, et al. Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death. Cell Prolif, 2019, 52(2): e12568.
32.	Cen D, Brayton D, Shahandeh B, et al. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem, 2004, 47(27): 6914-6920.
33.	Kirshner JR, He S, Balasubramanyam V, et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther, 2008, 7(8): 2319-2327.
34.	Nagai M, Vo NH, Shin Ogawa L, et al. The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. Free Radic Biol Med, 2012, 52(10): 2142-2150.
35.	Pan M, Zheng Q, Yu Y, et al. Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. Nat Commun, 2021, 12(1): 121.
36.	Skrott Z, Majera D, Gursky J, et al. Disulfiram's anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase. Oncogene, 2019, 38(40): 6711-6722.
37.	Mangala LS, Zuzel V, Schmandt R, et al. Therapeutic targeting of ATP7B in ovarian carcinoma. Clin Cancer Res, 2009, 15(11): 3770-3780.
38.	Samimi G, Safaei R, Katano K, et al. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res, 2004, 10(14): 4661-4669.
39.	Wu G, Peng H, Tang M, et al. ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression. EBioMedicine, 2021, 71: 103558.
40.	Han J, Hu Y, Liu S, et al. A newly established cuproptosis-associated long non-coding rna signature for predicting prognosis and indicating immune microenvironment features in soft tissue sarcoma. J Oncol, 2022, 2022: 8489387.
41.	Lv H, Liu X, Zeng X, et al. Comprehensive analysis of cuproptosis-related genes in immune infiltration and prognosis in melanoma. Front Pharmacol, 2022, 13: 930041.
42.	Xu S, Liu D, Chang T, et al. Cuproptosis-associated lncRNA establishes new prognostic profile and predicts immunotherapy response in clear cell renal cell carcinoma. Front Genet, 2022, 13: 938259.
43.	Ji ZH, Ren WZ, Wang HQ, et al. Molecular subtyping based on cuproptosis-related genes and characterization of tumor microenvironment infiltration in kidney renal clear cell carcinoma. Front Oncol, 2022, 12: 919083.
44.	Zhang Z, Zeng X, Wu Y, et al. Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in hepatocellular carcinoma. Front Immunol, 2022, 13: 925618.
45.	Tang R, Xu J, Zhang B, et al. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol, 2020, 13(1): 110.
46.	Jiang G-M, Tan Y, Wang H, et al. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol Cancer, 2019, 18(1): 17.
47.	Zhang HC, Deng SH, Pi YN, et al. Identification and validation in a novel quantification system of ferroptosis patterns for the prediction of prognosis and immunotherapy response in left- and right-sided colon cancer. Front Immunol, 2022, 13: 855849.
48.	Wang YY, Shi L-, Zhu Z-, et al. A new pyroptosis model can predict the immunotherapy response and immune microenvironment characteristics and prognosis of patients with cutaneous melanoma based on TCGA and GEO databases. Ann Transl Med, 2022, 10(6): 353.
49.	Song W, Ren J, Xiang R, et al. Identification of pyroptosis-related subtypes, the development of a prognosis model, and characterization of tumor microenvironment infiltration in colorectal cancer. Oncoimmunol, 2021, 10(1): 1987636.
50.	Lu Y, Luo X, Wang Q, et al. A novel necroptosis-related lncrna signature predicts the prognosis of lung adenocarcinoma. Front Genet, 2022, 13: 862741.
51.	Leone RD, Powell JD. Metabolism of immune cells in cancer. Nat Rev Cancer, 2020, 20(9): 516-531.
52.	Kaiser AM, Gatto A, Hanson KJ, et al. p53 governs an AT1 differentiation programme in lung cancer suppression. Nature, 2023, 619(7971): 851-859.
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54.	Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol, 2018, 15(1): 13-30.
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59.	Castellanos E, Feld E, Horn L. Driven by mutations: The Predictive value of mutation subtype in egfr-mutated non-small cell lung cancer. J Thorac Oncol, 2017, 12(4): 612-623.
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69.	Werlenius K, Kinhult S, Solheim TS, et al. Effect of disulfiram and copper plus chemotherapy vs chemotherapy alone on survival in patients with recurrent glioblastoma: A randomized clinical trial. JAMA Netw Open, 2023, 6(3): e234149.
70.	Lu X, Chen X, Lin C, et al. Elesclomol loaded copper oxide nanoplatform triggers cuproptosis to enhance antitumor immunotherapy. Adv Sci (Weinh), 2024, 11(18): e2309984.
71.	Xia J, Hu C, Ji Y, et al. Copper-loaded nanoheterojunction enables superb orthotopic osteosarcoma therapy via oxidative stress and cell cuproptosis. ACS Nano, 2023, 17(21): 21134-21152.

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-Mutated NSCLC. N Engl J Med, 2023, 389(2): 137-147.
3. Hong L, Negrao MV, Dibaj SS, et al. Programmed death-ligand 1 heterogeneity and its impact on benefit from immune checkpoint inhibitors in NSCLC. J Thorac Oncol, 2020, 15(9): 1449-1459.
4. Mok TSK, Wu YL, Kudaba L, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet, 2019, 393(10183): 1819-1830.
5. Festa RA, Thiele DJ. Copper: An essential metal in biology. Curr Biol, 2011, 21(21): R877-R883.
6. Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
7. Cobine PA, Brady DC. Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death. Mol Cell, 2022, 82(10): 1786-1787.
8. Porporato PE, Filigheddu N, Pedro JMB-S, et al. Mitochondrial metabolism and cancer. Cell Res, 2018, 28(3): 265-280.
9. Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol, 2017, 24(9): 1161-1180.
10. Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol, 2019, 15(7): 681-689.
11. Buccarelli M, D'Alessandris QG, Matarrese P, et al. Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth. J Exp Clin Cancer Res, 2021, 40(1): 228.
12. Raggi C, Taddei ML, Sacco E, et al. Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma. J Hepatol, 2021, 74(6): 1373-1385.
13. Peng X, Zhu J, Liu S, et al. Signature construction and molecular subtype identification based on cuproptosis-related genes to predict the prognosis and immune activity of patients with hepatocellular carcinoma. Front Immunol, 2022, 13: 990790.
14. Zhang Y, Chen K, Wang L, et al. Identification and validation of a prognostic signature of cuproptosis-related genes for esophageal squamous cell carcinoma. Aging (Albany NY), 2023, 15(17): 8993-9021.
15. Luo L, Li A, Fu S, et al. [Cuproptosis-related immune gene signature predicts clinical benefits from anti-PD-1/PD-L1 therapy in non-small-cell lung cancer. Immunol Res, 2023, 71(2): 213-228.
16. Tang Y, Wang T, Li Q, et al. A cuproptosis score model and prognostic score model can evaluate clinical characteristics and immune microenvironment in NSCLC. Cancer Cell Int, 2024, 24(1): 68.
17. Ma C, Gu Z, Ding W, et al. Crosstalk between copper homeostasis and cuproptosis reveals a lncRNA signature to prognosis prediction, immunotherapy personalization, and agent selection for patients with lung adenocarcinoma. Aging (Albany NY), 2023, 15(22): 13504-13541.
18. Luo D, Wang X, Feng W. Comprehensive analysis of cuproptosis and copper homeostasis genotyping and related immune land scape in lung adenocarcinoma. Sci Rep, 2023, 13(1): 16554.
19. Xu M, Mu J, Wang J, et al. Construction and validation of a cuproptosis-related lncRNA signature as a novel and robust prognostic model for colon adenocarcinoma. Front Oncol, 2022, 12: 961213.
20. Hasinoff BB, Wu X, Yadav AA, et al. Cellular mechanisms of the cytotoxicity of the anticancer drug elesclomol and its complex with Cu(II). Biochem Pharmacol, 2015, 93(3): 266-276.
21. Jiao Y, Hannafon BN, Ding W-Q. Disulfiram's anticancer activity: evidence and mechanisms. Anticancer Agents Med Chem, 2016, 16(11): 1378-1384.
22. Lönnerdal B. Intestinal regulation of copper homeostasis: A developmental perspective. Am J Clin Nutr, 2008, 88(3): 846S-850S.
23. Lutsenko S. Dynamic and cell-specific transport networks for intracellular copper ions. J Cell Sci, 2021, 134(21): jcs240523.
24. Hernandez S, Tsuchiya Y, García-Ruiz JP, et al. ATP7B copper-regulated traffic and association with the tight junctions: copper excretion into the bile. Gastroenterology, 2008, 134(4): 1215-1223.
25. Cobine PA, Moore SA, Leary SC. Getting out what you put in: Copper in mitochondria and its impacts on human disease. Biochim Biophys Acta Mol Cell Res, 2021, 1868(1): 118867.
26. Saleh SAK, Adly HM, Abdelkhaliq AA, et al. Serum levels of selenium, zinc, copper, manganese, and iron in prostate cancer patients. Curr Urol, 2020, 14(1): 44-49.
27. Pavithra V, Sathisha TG, Kasturi K, et al. Serum levels of metal ions in female patients with breast cancer. J Clin Diagn Res, 2015, 9(1): BC25-Bc27.
28. Basu S, Singh MK, Singh TB, et al. Heavy and trace metals in carcinoma of the gallbladder. World J Surg, 2013, 37(11): 2641-2646.
29. Wang W, Wang X, Luo J, et al. Serum copper level and the copper-to-zinc ratio could be useful in the prediction of lung cancer and its prognosis: A case-control study in northeast china. Nutr Cancer, 2021, 73(10): 1908-1915.
30. Lossow K, Schwarz M, Kipp AP. Are trace element concentrations suitable biomarkers for the diagnosis of cancer? Redox Biol, 2021, 42: 101900.
31. Yu Z, Zhou R, Zhao Y, et al. Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death. Cell Prolif, 2019, 52(2): e12568.
32. Cen D, Brayton D, Shahandeh B, et al. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem, 2004, 47(27): 6914-6920.
33. Kirshner JR, He S, Balasubramanyam V, et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther, 2008, 7(8): 2319-2327.
34. Nagai M, Vo NH, Shin Ogawa L, et al. The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. Free Radic Biol Med, 2012, 52(10): 2142-2150.
35. Pan M, Zheng Q, Yu Y, et al. Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. Nat Commun, 2021, 12(1): 121.
36. Skrott Z, Majera D, Gursky J, et al. Disulfiram's anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase. Oncogene, 2019, 38(40): 6711-6722.
37. Mangala LS, Zuzel V, Schmandt R, et al. Therapeutic targeting of ATP7B in ovarian carcinoma. Clin Cancer Res, 2009, 15(11): 3770-3780.
38. Samimi G, Safaei R, Katano K, et al. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res, 2004, 10(14): 4661-4669.
39. Wu G, Peng H, Tang M, et al. ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression. EBioMedicine, 2021, 71: 103558.
40. Han J, Hu Y, Liu S, et al. A newly established cuproptosis-associated long non-coding rna signature for predicting prognosis and indicating immune microenvironment features in soft tissue sarcoma. J Oncol, 2022, 2022: 8489387.
41. Lv H, Liu X, Zeng X, et al. Comprehensive analysis of cuproptosis-related genes in immune infiltration and prognosis in melanoma. Front Pharmacol, 2022, 13: 930041.
42. Xu S, Liu D, Chang T, et al. Cuproptosis-associated lncRNA establishes new prognostic profile and predicts immunotherapy response in clear cell renal cell carcinoma. Front Genet, 2022, 13: 938259.
43. Ji ZH, Ren WZ, Wang HQ, et al. Molecular subtyping based on cuproptosis-related genes and characterization of tumor microenvironment infiltration in kidney renal clear cell carcinoma. Front Oncol, 2022, 12: 919083.
44. Zhang Z, Zeng X, Wu Y, et al. Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in hepatocellular carcinoma. Front Immunol, 2022, 13: 925618.
45. Tang R, Xu J, Zhang B, et al. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol, 2020, 13(1): 110.
46. Jiang G-M, Tan Y, Wang H, et al. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol Cancer, 2019, 18(1): 17.
47. Zhang HC, Deng SH, Pi YN, et al. Identification and validation in a novel quantification system of ferroptosis patterns for the prediction of prognosis and immunotherapy response in left- and right-sided colon cancer. Front Immunol, 2022, 13: 855849.
48. Wang YY, Shi L-, Zhu Z-, et al. A new pyroptosis model can predict the immunotherapy response and immune microenvironment characteristics and prognosis of patients with cutaneous melanoma based on TCGA and GEO databases. Ann Transl Med, 2022, 10(6): 353.
49. Song W, Ren J, Xiang R, et al. Identification of pyroptosis-related subtypes, the development of a prognosis model, and characterization of tumor microenvironment infiltration in colorectal cancer. Oncoimmunol, 2021, 10(1): 1987636.
50. Lu Y, Luo X, Wang Q, et al. A novel necroptosis-related lncrna signature predicts the prognosis of lung adenocarcinoma. Front Genet, 2022, 13: 862741.
51. Leone RD, Powell JD. Metabolism of immune cells in cancer. Nat Rev Cancer, 2020, 20(9): 516-531.
52. Kaiser AM, Gatto A, Hanson KJ, et al. p53 governs an AT1 differentiation programme in lung cancer suppression. Nature, 2023, 619(7971): 851-859.
53. Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: A lifeguard with a licence to kill. Nat Rev Mol Cell Biol, 2015, 16(7): 393-405.
54. Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol, 2018, 15(1): 13-30.
55. Reck M, Carbone DP, Garassino M, et al. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol, 2021, 32(9): 1101-1110.
56. Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A, 2010, 107(19): 8788-8793.
57. Xia M, Li X, Diao Y, et al. Targeted inhibition of glutamine metabolism enhances the antitumor effect of selumetinib in KRAS-mutant NSCLC. Transl Oncol, 2021, 14(1): 100920.
58. Aubert L, Nandagopal N, Steinhart Z, et al. Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer. Nat Commun, 2020, 11(1): 3701.
59. Castellanos E, Feld E, Horn L. Driven by mutations: The Predictive value of mutation subtype in egfr-mutated non-small cell lung cancer. J Thorac Oncol, 2017, 12(4): 612-623.
60. De Rosa V, Iommelli F, Monti M, et al. Reversal of warburg effect and reactivation of oxidative phosphorylation by differential inhibition of EGFR Signaling pathways in non-small cell lung cancer. Clin Cancer Res, 2015, 21(22): 5110-5120.
61. Wang H, Hu Q, Chen Y, et al. Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Nat Commun, 2024, 15(1): 4195.
62. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med, 2022, 386(21): 1973-1985.
63. Voli F, Valli E, Lerra L, et al. Intratumoral copper modulates PD-L1 expression and influences tumor immune evasion. Cancer Res, 2020, 80(19): 4129-4144.
64. Guo B, Yang F, Zhang L, et al. Cuproptosis induced by ROS Responsive nanoparticles with elesclomol and copper combined with αPD-L1 for enhanced cancer immunotherapy. Adv Mater, 2023, 35(22): e2212267.
65. Nechushtan H, Hamamreh Y, Nidal S, et al. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist, 2015, 20(4): 366-367.
66. Mego M, Svetlovska D, Angelis V D, et al. Phase Ⅱ study of disulfiram and cisplatin in refractory germ cell tumors. The GCT-SK-006 phaseⅡtrial. Invest New Drugs, 2022, 40(5): 1080-1086.
67. Zheng X, Liu Z, Mi M, et al. Disulfiram improves the anti-PD-1 therapy efficacy by regulating PD-L1 expression via epigenetically reactivation of IRF7 in triple negative breast cancer. Front Oncol, 2021, 11: 734853.
68. Guo W, Jia L, Xie L, et al. Turning anecdotal irradiation-induced anticancer immune responses into reproducible in situ cancer vaccines via disulfiram/copper-mediated enhanced immunogenic cell death of breast cancer cells. Cell Death Dis, 2024, 15(4): 298.
69. Werlenius K, Kinhult S, Solheim TS, et al. Effect of disulfiram and copper plus chemotherapy vs chemotherapy alone on survival in patients with recurrent glioblastoma: A randomized clinical trial. JAMA Netw Open, 2023, 6(3): e234149.
70. Lu X, Chen X, Lin C, et al. Elesclomol loaded copper oxide nanoplatform triggers cuproptosis to enhance antitumor immunotherapy. Adv Sci (Weinh), 2024, 11(18): e2309984.
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