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].