Core Viewpoint - Drug resistance remains the most severe challenge in targeted therapy for lung cancer, with cuproptosis showing promise in overcoming this resistance, although its potential in targeted treatment has yet to be fully explored [1]. Group 1: Research Findings - A study published by researchers from the Chinese Academy of Medical Sciences indicates that inducing cuproptosis enhances the sensitivity of lung cancer to the targeted drug osimertinib and overcomes drug resistance [2][3]. - The research team observed a high degree of synergistic effect between CuET (copper death induction) and osimertinib, indicating that cuproptosis induction increases the anticancer efficacy of osimertinib [5]. - In a secondary screening, cuproptosis was identified as a major vulnerability in osimertinib-resistant cell lines, with the key driver factor FDX1 significantly upregulated in these resistant cells [6]. Group 2: Mechanism of Action - The study highlights that the activation of bypass pathways, particularly involving AKT phosphorylation, is the most common mechanism of drug resistance, accounting for approximately 46% of cases [7]. - Induction of cuproptosis in combination with osimertinib significantly reduced p-AKT levels while increasing the expression of cuproptosis markers and apoptosis markers, suggesting a mechanism for overcoming drug resistance [7]. - In patient-derived organoid models, the combination of CuET and osimertinib outperformed single-agent treatments, demonstrating the potential for enhanced therapeutic efficacy [8]. Group 3: Clinical Implications - The findings suggest that targeting cuproptosis could be a promising strategy to overcome osimertinib resistance, linking it to the commonly overlooked AKT activation mechanism [10]. - With the development of copper ion carriers and nanoparticle delivery systems being actively pursued, these discoveries provide a pathway for clinical translation, necessitating prospective trials to evaluate safety and efficacy [10].

撰文 | 王聪 编辑 | 王多鱼 排版 | 水成文 众所周知，多细胞生物在发育过程中，存在着多种预定的、受到精确控制的 细胞程序性死亡 ，例如 细胞凋亡 （Apoptosis） 、 程序性坏死 （Necroptosis） 、 细胞焦亡 （Pyroptosis） ，以及 铁死亡 （Ferroptosis） 等。 2022 年 3 月 17 日，哈佛-MIT博德研究所 Todd Golub 教授团队 在国际顶尖学术期刊 Science 上发表论文。该研究 首次揭示了一种 铜依赖的受控细胞死亡方式，并将其命名为—— Cuprotosis （铜死亡） 。这种铜依赖的细胞死亡是通 过 铜离子 与 线粒体呼吸 中的 三羧酸循环 （TCA） 中的 硫辛酰化 成分直接结合而发生的，导致 硫辛酰化 蛋白质聚 集和随后的铁硫簇蛋白下调，从而导致蛋白质毒性应激并最终导致细胞死亡。 2025 年 11 月 19 日，墨尔本大学 Lev M. Kats 团队在国际顶尖学术期刊 Cell 上发表了题为 ： Inhibition of heme biosynthesis triggers cuproptosis in acute myel ...

Core Viewpoint - The article discusses the emerging focus on metabolic cell death as a new frontier in cancer therapy, highlighting the significance of ferroptosis, cuproptosis, and disulfidptosis as potential therapeutic targets against cancer cells that evade traditional cell death pathways [3][4][5]. Group 1: Metabolic Cell Death Mechanisms - Metabolic cell death is characterized by the collapse of metabolic homeostasis, leading to irreversible cell death due to nutrient deprivation or the accumulation of harmful metabolites [3]. - Ferroptosis, discovered in 2012, is an iron-dependent cell death mechanism that results from uncontrolled lipid peroxidation, leading to membrane damage [8]. - Cuproptosis, identified in 2022, is a copper-dependent cell death mechanism where excess copper ions induce protein toxicity by binding to fatty acylated proteins in mitochondria [14]. - Disulfidptosis, proposed in 2023, occurs when cystine accumulation leads to the collapse of the actin cytoskeleton under conditions of glucose deprivation or NADPH depletion [19]. Group 2: Cancer Treatment Implications - Targeting metabolic cell death pathways presents a unique opportunity to exploit cancer cells' vulnerabilities, particularly through the mechanisms of ferroptosis, cuproptosis, and disulfidptosis [5][26]. - The interplay between these pathways suggests that combined interventions could enhance therapeutic efficacy and overcome drug resistance in cancer treatment [24][26]. - Establishing verifiable biomarker systems is crucial for advancing clinical applications and achieving precise patient stratification and treatment [26].

Core Viewpoint - The article discusses a novel strategy to improve CAR-T cell therapy for osteosarcoma by utilizing cuproptosis, which enhances the efficacy of the treatment in a challenging tumor microenvironment [3][4][11]. Group 1: Osteosarcoma and Current Treatment Challenges - Osteosarcoma is a common malignant tumor with a low survival rate of approximately 15%-17% for patients receiving only surgical treatment, and a stagnated 5-year survival rate of about 60% for those undergoing combined surgery and chemotherapy over the past 30 years [1]. - Traditional chemotherapy often leads to drug resistance and tumor recurrence, highlighting the urgent need for improved treatment strategies [1]. Group 2: Novel Research Findings - A study published by a team from Southern Medical University proposes a new approach using cuproptosis to enhance CAR-T cell therapy in osteosarcoma [2]. - The research indicates that copper death can lower PD-L1 expression in osteosarcoma cells, which is positively correlated with copper death-related gene expression [8][11]. - The study developed a biocompatible nanodrug composed of tetrahedral framework nucleic acids (tFNA), elesclomol-Cu, and anti-PD-L1 antibodies to induce copper death and block the PD-1-PD-L1 signaling axis, thereby reshaping the immunosuppressive tumor microenvironment [3][9]. Group 3: Implications for CAR-T Cell Therapy - The results demonstrate that the use of this nanodrug significantly enhances CAR-T cell infiltration and anti-tumor activity in both in situ and recurrent osteosarcoma models [10]. - This research provides insights into the relationship between copper metabolism and PD-L1 expression, offering a potential universal method to improve adoptive cell therapy for solid tumors [4].

Core Viewpoint - Copper is an essential element for life, playing a critical role as a cofactor in various enzymatic processes. The discovery of cuproptosis, a new form of programmed cell death linked to copper ion homeostasis, presents significant implications for cancer therapy [1][2]. Group 1: Copper and Cuproptosis - Copper is a vital trace element in human life, necessary for various biological functions, but can become toxic at elevated levels, leading to cell death [1]. - Cuproptosis, identified in 2022, is characterized by the disruption of copper ion homeostasis and abnormal regulation of protein acylation, resulting in unique cell death pathways [1]. Group 2: Research and Development - A research team from Tianjin University published a study on July 11, 2025, focusing on a covalent organic framework designed to induce intracellular copper accumulation for cuproptosis cancer therapy [3]. - The study developed a nano-system, P1+P2@COF@F127-D, which utilizes endogenous copper to achieve copper-based cancer treatment through a cascade reaction [6]. Group 3: Mechanism of Action - The nano-system initiates a cascade reaction by introducing a copper output inhibitor, DC_AC50, which specifically increases intracellular levels of cuprous ions (Cu+) in cancer cells, leading to irreversible cuproptosis [6][10]. - The system employs small molecule inhibitors of glutaminase-1 (GLS1) encapsulated in a glutathione-responsive covalent organic framework, facilitating the release of DC_AC50 and the GLS1 inhibitors upon cellular uptake [7]. Group 4: Highlights of the Study - The research successfully developed a copper death therapy nano-system that does not require exogenous copper, instead utilizing endogenous copper to trigger a copper-glutathione-mediated intracellular cascade reaction, amplifying the anti-tumor effect [10][11]. - The design features a self-reinforcing feedback loop characterized by increased Cu+, enhanced GLS1 inhibitor production, and reduced glutathione (GSH) levels, further promoting the accumulation of Cu+ and enhancing the therapeutic effect [7][11].

Core Viewpoint - The research highlights a novel form of programmed cell death called cuproptosis, which is linked to copper ion overload and its impact on mitochondrial function, particularly in group-3 medulloblastomas, a type of malignant brain tumor common in children [1][2][6]. Group 1: Copper and Cell Death Mechanism - Copper is an essential element for life, but its excess can lead to toxicity and cell death [1]. - Cuproptosis is characterized by the disruption of key enzymes in the mitochondrial tricarboxylic acid cycle due to copper overload, leading to mitochondrial dysfunction and unique cell death pathways [1]. Group 2: Medulloblastoma Characteristics - Medulloblastoma is the most common malignant brain tumor in children, classified into four subgroups: SHH, WNT, group-3, and group-4, with group-3 having the worst prognosis [4]. - The most common driver event in group-3 medulloblastoma is the amplification or overexpression of the MYC gene, which is associated with poor outcomes, as over half of the patients do not achieve progression-free survival after five years [4]. Group 3: Research Findings - The study found that the expression of DLAT, a component of the pyruvate dehydrogenase complex, is upregulated in group-3 medulloblastomas and is induced by c-MYC [5][6]. - Inhibition of IDH1 can lower c-MYC and DLAT levels, suggesting a potential therapeutic target [5][6]. - DLAT is identified as a key regulator of cuproptosis, and its expression correlates with increased sensitivity to copper-induced cell death in group-3 medulloblastoma cells [6]. Group 4: Therapeutic Implications - The copper ion carrier elesclomol has shown toxic effects on group-3 medulloblastoma both in vitro and in vivo, indicating its potential as a treatment option [5][6]. - The research suggests a vulnerability in group-3 medulloblastomas that can be targeted through the modulation of IDH1/c-MYC and DLAT levels to induce cuproptosis [9].