Review ArticleReview
Open Access

Innovative cross-intervention: copper ions and metabolic pathways in cancer therapy

Lili Niu, Wei Su, Lixia Ju, Jun Xiang, Zhou Yang and Bing Yao
Cancer Biology & Medicine January 2026, 20250198; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0198

Abstract

Copper ions are essential for cellular function but can induce cytotoxic effects when dysregulated. This review explores the multifaceted role of copper in cancer metabolism with a focus on the novel concept of cuproptosis, a regulated form of cell death triggered by copper accumulation. The mechanisms underlying copper homeostasis are detailed, including dietary absorption, systemic distribution, and intracellular utilization. Key transporters, such as copper transporter 1 (CTR1) and ATPase copper transporting alpha/b (ATP7A/B), are highlighted. Cancer cells often exhibit elevated copper levels, supporting proliferation and metastasis through pro-tumorigenic pathways. Recent studies have shown that disrupting copper homeostasis can induce cuproptosis, which is characterized by the aggregation of lipoylated mitochondrial proteins and disruption of iron-sulfur cluster biogenesis. Advances in copper-based nanotechnology have enabled targeted delivery of copper to tumors, enhancing therapeutic efficacy through synergistic effects with reactive oxygen species (ROS) generation and immunomodulation. However, the hypoxic tumor microenvironment poses significant challenges by upregulating copper-sequestering proteins and downregulating key cuproptosis mediators. Future directions include integrating multi-omics approaches to identify novel therapeutic targets and developing combination therapies to overcome hypoxia-induced resistance. This review provides a comprehensive overview of copper metabolism in cancer, emphasizing the potential of cuproptosis induction as a powerful strategy for oncologic intervention.

keywords

Introduction

Copper is an essential redox-active micronutrient that serves as a critical cofactor for a vast array of enzymes governing fundamental biological processes, including mitochondrial respiration, antioxidant defense, and signaling cascades1. However, excessive intracellular copper can catalyze the generation of highly reactive hydroxyl radicals via the Fenton reaction, leading to severe oxidative damage to DNA, proteins, and lipids, and ultimately triggering cytotoxic effects2. To maintain this delicate balance, organisms have evolved a sophisticated regulatory network comprising copper chaperones, transporters (e.g., CTR1 and ATP7A/B), and storage proteins [e.g., metallothioneins (MTs)], which coordinate the absorption, distribution, utilization, and excretion of copper3.

Cancer cells often exhibit elevated copper levels, which support proliferation, angiogenesis, and metastasis by activating pro-tumorigenic signaling pathways and enzymes4,5. This copper dependency, termed “cuproplasia,” positions copper as an attractive target for anticancer therapy. Traditional strategies have focused on copper chelation [e.g., with tetrathiomolybdate (TTM)] to deplete bioavailable copper and suppress tumor growth5. In a fascinating paradox, forcing cancer cells to accumulate excess copper can also be lethal. Although copper-induced cell death was observed decades ago6, the precise mechanism was elusive until the recent groundbreaking work by Tsvetkov et al.1, who defined a novel, regulated form of cell death (cuproptosis).

Cuproptosis is mechanistically distinct from other programmed cell death pathways, such as apoptosis, ferroptosis, and necroptosis, because cuproptosis is not inhibited by corresponding specific inhibitors1. The translational potential of inducing cuproptosis in tumors is significant, primarily through copper ionophores, like elesclomol (ES)1. Furthermore, advances in nanotechnology have enabled the development of sophisticated copper-based nanoparticles that enhance tumor-selective copper delivery, synergizing cuproptosis with ROS generation and immunomodulation for improved antitumor efficacy5. However, a major therapeutic challenge arises from the hypoxic tumor microenvironment, which activates hypoxia inducible factor-1α (HIF-1α) and confers resistance to cuproptosis by upregulating copper-sequestering MTs (e.g., MT2A) and downregulating key mediators, like dihydrolipoylS-acetyltransferase (DLAT)7. Overcoming this resistance necessitates innovative combination strategies. As shown in Figure 1, this review comprehensively summarizes the fundamental principles of systemic and cellular copper homeostasis, elaborates on the unique molecular mechanisms of cuproptosis, and critically examines the latest advances in targeting copper metabolism for cancer therapy. The challenges posed by the tumor microenvironment are discussed and future directions are explored, including the integration of multi-omics approaches and combination therapies, to fully realize the potential of cuproptosis induction as a powerful weapon in the oncotherapeutic arsenal.

Figure 1
Figure 1

Schematic summary of the dual roles of copper in cancer biology and copper-modulating therapies. This figure illustrates the complex relationship between copper in cancer biology and potential copper-modulating therapies, showing how copper, through copper-dependent cell death pathways, contributes to malignant progression. Various therapies, such as nanoparticles, chelators, and ionophores, are shown as strategies to disrupt copper trafficking, selectively killing cancer cells. The figure also highlights future directions in therapy, including immunotherapy/gene therapy, multi-metal targeting, and artificial metalloenzymes to further enhance cancer treatment. DSF, disulfiram; ES, elesclomo.

Copper homeostasis and metabolic regulation

Copper, an essential redox-active micronutrient, serves as a critical cofactor for enzymes governing fundamental biological processes, including mitochondrial respiration, antioxidant defense, and signaling cascades1. Although copper is an essential trace element for human body, excessive accumulation of copper can lead to the generation of hydroxyl radicals (·OH) via the Fenton reaction (Cu+ + H2O2 → Cu2+ + ·OH + OH−). The hydroxyl radical is a highly reactive ROS capable of inducing oxidative damage to DNA, proteins, and lipids, thereby triggering cytotoxic effects2. To prevent such adverse outcomes, copper levels in the body are tightly regulated by a sophisticated network of copper-related proteins, including copper-dependent enzymes, copper chaperones, and membrane-bound transporters. These proteins collectively govern copper absorption, excretion, and intracellular utilization to maintain systemic copper homeostasis3.

Dietary absorption and systemic distribution

The concentration of free copper ions is relatively low in the human body because most copper is either stored in a bound form or functions as a cofactor by associating with proteins or other biomolecules8. Dietary copper is primarily absorbed via the intestinal epithelium with the duodenum serving as the main site of absorption9. Dietary copper predominantly exists in the Cu2+ form but only the reduced Cu+ form can be effectively absorbed and utilized by the body. As illustrated in Figure 1, ingested Cu2+ is initially reduced to Cu+ by metal reductases, such as six-transmembrane epithelial antigen of the prostate (STEAP) or duodenal cytochrome b (Dcytb), after which Cu2+ enters intestinal epithelial cells via copper transporter 1 (CTR1)10,11. CTR1 is the principal mediator of intestinal copper absorption and intestinal-specific knockout of CTR1 has been shown to result in systemic copper deficiency12. The expression of CTR1 is modulated by the body copper status, it is downregulated under conditions of copper excess and upregulated in states of deficiency13. In addition to CTR1, other transporters, such as the low-affinity copper transporter 2 (CTR2)14 and divalent metal transporter 1 (DMT1)15, also contribute to copper uptake. Absorbed copper is transported into the bloodstream via ATP7A located on the basolateral membrane of intestinal epithelial cells16. Most copper in the blood binds to ceruloplasmin, although a minor fraction associates with albumin, transferrin, and free amino acids. This copper-bound ceruloplasmin is then transported to the liver via the portal venous system.

Hepatic storage, utilization, and excretion

Hepatocytes primarily take up copper through the CTR1 and the liver serves as the primary site for copper storage and excretion17. As illustrated in Figure 1, copper binds to glutathione (GSH) within the cytoplasm and is subsequently transferred to MT. Both GSH and MT contain abundant thiol groups, which confer a strong affinity for copper. MT1 and MT2 are the principal copper-binding proteins in the liver and serve as major copper storage sites18. MT3, which is predominantly expressed in the central nervous system, also has a role in maintaining copper homeostasis19. Copper is involved in the biosynthesis of ceruloplasmin within hepatocytes. Copper-bound ceruloplasmin is secreted into the bloodstream and delivered to specific tissues or organs, where copper-bound ceruloplasmin participates in various catalytic physiologic processes8. When systemic copper levels exceed physiologic requirements, hepatocytes transport excess copper into bile via ATP7B, where it is excreted into the intestine through the biliary tract and ultimately eliminated from the body via feces. Biliary excretion constitutes the primary route of copper elimination20. In summary, systemic copper metabolism is predominantly regulated by intestinal absorption and hepatic excretion. Under conditions of copper excess, absorption decreases and excretion increases, whereas the opposite pattern occurs during copper deficiency.

Intracellular copper trafficking and utilization

Copper primarily participates in physiologic cellular processes in the form of Cu+. CTR1 serves as the primary pathway for cellular copper uptake21. As illustrated in Figure 2, copper can interact with various copper chaperones upon entering the cell, including cytochrome c oxidase copper chaperone 11/17 (COX11/17), copper chaperone for superoxide dismutase (CCS), and antioxidant protein 1 (ATOX1). These chaperones facilitate the delivery of copper to specific target proteins or subcellular compartments, where copper performs essential biological functions. The synthesis of cytochrome c oxidase (CCO) involves several key steps and molecular components. CCO consists of two core subunits in humans [cytochrome c oxidase subunits 1 (COX1) and 2 (COX2)], which bind copper ions at the CuB and CuA sites, respectively22. COX17 is responsible for transporting copper from the cytoplasm to the mitochondrial intermembrane space23. Copper ions are subsequently delivered to the COX2 subunit via cytochrome c oxidase synthesis proteins 1 and 2 (SCO1/2) or to the COX1 subunit through COX1124,25. These copper-binding events are essential for the proper functioning of the respiratory chain and oxidative phosphorylation. Mutations in COX17 or SCO1/2 have been shown to reduce CCO activity, thereby impairing cellular energy metabolism26,27. ATOX1 mediates the transfer of copper to ATP7A/B, which are the primary transporters responsible for copper efflux from cells. The localization and functional activities of ATP7A/B are dynamically regulated28. Under physiologic intracellular copper concentrations, these transporters reside in the trans-Golgi network (TGN), where they facilitate the transport of copper ions from the cytoplasm into the luminal compartment of the TGN. Upon elevation of intracellular copper levels, these proteins translocate from the TGN to the plasma membrane, enabling the excretion of excess copper from the cell. ATP7A and ATP7B exhibit distinct expression patterns. ATP7A is broadly expressed across most tissues and organs, whereas ATP7B is predominantly expressed in the liver29. Notably, intestinal epithelial cells also express ATP7B, which primarily functions to sequester copper within intracellular vesicles, thereby maintaining copper homeostasis30. ATP7B can relocate from the TGN to lysosomes when hepatocyte copper levels are excessive, followed by copper excretion into bile via exocytosis. Alternatively, ATP7B can also translocate to the apical membrane to directly excrete copper into bile31. Consequently, mutations in ATP7A or ATP7B may lead to disturbances in copper metabolism, resulting in intracellular copper accumulation and the development of Menkes and Wilson’s diseases, respectively20,32. ATOX1 binds to copper within the cell nucleus and functions as a transcription factor that promotes gene expression29. Superoxide dismutase 1 (SOD1), commonly referred to as copper-zinc superoxide dismutase, catalyzes the conversion of superoxide anions (O2·−) into hydrogen peroxide (2O2·− + H+ → H2O2 + O2)33. O2·− has a key role in the production of ROS within the body. CCS interacts with CTR1 and SOD1 to form the CTR1-CCS-SOD1 complex, which facilitates the transfer of copper to SOD1, thereby activating SOD1 and modulating intracellular oxidative stress levels34.

Figure 2
Figure 2

Schematic diagram of cellular copper metabolism. This figure illustrates the detailed process of copper metabolism within the cell. ① Extracellular copper exists primarily as Cu2+ in mammalian cells, which is reduced to Cu+ by membrane-associated metalloreductases prior to cellular uptake via the high-affinity copper transporter, CTR1. ② Copper is trafficked to specific intracellular compartments in the cytoplasm by dedicated chaperones and storage molecules. Copper can be buffered by binding to GSH and sequestered by MT1/2 to maintain homeostasis. ③ The chaperone, CCS, delivers Cu+ to SOD1, promoting the formation of the CTR1–CCS–SOD1 complex and activating SOD1 to catalyze the dismutation of O2·−, thereby mitigating oxidative stress. ④ COX17 delivers copper to the intermembrane space for mitochondrial utilization, where SCO1/2 and COX11 facilitate copper incorporation into the CuA site of COX2 and the CuB site of COX1, respectively, which is essential for the assembly and function of CCO. ⑤ In addition, the chaperone ATOX1 transfers Cu+ to ATP7A/B transporters in the TGN. Under normal conditions, these ATPases metallate cuproenzymes within the secretory pathway, when copper is overloaded, the ATPases relocalize to the plasma membrane or lysosomes to mediate efflux with ATP7A being widely expressed and ATP7B functioning primarily in hepatic and intestinal copper excretion into bile. ⑥ In addition, ATOX1 can deliver copper into the nucleus, where ATOX1 acts as a copper-dependent transcription factor to modulate gene expression. Collectively, these coordinated pathways ensure precise copper homeostasis, achieving a balance between its essential roles in cellular biochemistry and the prevention of cytotoxicity. ATP7A/B, ATPase copper transporting alpha/beta (also known as Menkes and Wilson disease protein, respectively); CCS, copper chaperone for SOD1; COX11, cytochrome c oxidase copper chaperone 11; COX17, cytochrome c oxidase assembly protein 17; CTR1, copper transporter 1; Cu, copper; Cu+, copper (I) ion (cuprous ion); Cu2+, copper (II) ion (cupric ion); CCO, cytochrome c oxidase; GSH, glutathione; MT1/2, metallothionein 1/2; O2·−, superoxide anion radical; SCO1/2, synthesis of cytochrome c oxidase 1/2; SOD1, superoxide dismutase 1; TGN, trans-Golgi network.

Copper ion homeostasis and tumor metabolism

The era of modern tumor metabolism research began with the discovery of a metabolic phenotype by Otto Warburg in 1924, which is now known as the Warburg effect35. The advent of high-throughput technologies and computational systems biology during the ensuing decades catalyzed a resurgence in cancer cell metabolism research. These innovative tools have enriched the understanding of the Warburg effect, enabling the identification of novel metabolic pathways and dependencies in cancer cells. Furthermore, the innovative tools have contributed to the development of potential therapeutic strategies aimed at targeting these metabolic alterations36. For example, the identification of metabolic reservoir cycles in cancer cells, including the storage and utilization of glycogen, triglycerides, and phosphocreatine, has yielded novel insights into the metabolic adaptability of cancer cells and potential therapeutic targets37. Numerous landmark discoveries have elucidated the role of copper in cancer metabolism. Xue et al. demonstrated that copper is intricately involved in cell death and autophagy induction in cancer cells38.

Moreover, copper-based nanoparticles have been developed for cancer therapy that take advantage of elevated levels of copper in tumor tissues. These nanoparticles trigger oxidative stress and cuproptosis in cancer cells as single agent therapy or in combination with other treatment modalities5 (Table 1). In addition to the therapeutic potential, copper ions (existing predominantly as Cu+ in the reducing cytosolic environment) have fundamental roles in cancer mitochondrial metabolism. Cu+-dependent enzymes (e.g., COX) sustain mitochondrial respiration, while Cu+/Cu2+ redox cycling catalyzes Fenton-like ROS generation. Perturbation of mitochondrial copper homeostasis can result in mitochondrial dysfunction and subsequent cell death in cancer cells39.

View this table:
Table 1

Main copper-related anti-cancer drugs

Recent advances in copper metabolism research have elucidated the pivotal role of copper transporters in cancer biology. The high-affinity copper transporter (CTR1), solute carrier family 31 member 1 (SLC31A1), not only maintains cellular copper homeostasis but also critically determines cisplatin sensitivity in cancer therapy40. Emerging studies revealed that additional metal transporters, including zinc transporter 1 (ZnT1/SLC30A1), participate in copper regulation and cuproptosis. Although primarily characterized as a zinc efflux transporter, ZnT1 has been confirmed to be involved in the modulation of Cu+ entry into cells and is essential for Cu2+-induced cell death41. Similarly, ATP7A/B are essential for maintaining cellular copper balance by transporting excess copper out of the cell. Recent studies have highlighted the significant roles of MT, particularly MT2A, MT1E, and MT1X isoforms, in copper metabolism42. Our research also indicated that HIF-1α induces the expression of MT2A and reduces mitochondrial copper accumulation by chelating cytoplasmic copper ions, thereby inhibiting cuproptosis7. Inhibition of these transporters disrupts cellular copper balance, which leads to elevated cellular copper levels and induces cell death43. Recent advances in the study of copper-dependent enzymes have highlighted the significance of copper-dependent enzymes as potential targets in cancer research. Enzymes, such as glutaminase C (GAC) and glutaminase 2 (GLS2), which facilitate the conversion of glutamine-to-glutamate, are pivotal in the glutamine dependency observed in cancer cells44. Elucidating the regulatory mechanisms and functions of these enzymes within the framework of copper metabolism may unveil novel therapeutic strategies. Furthermore, contemporary research has concentrated on the creation of artificial metalloenzymes and nanozymes for cancer treatment. By mimicking the catalytic activity of natural enzymes, these engineered enzymes exhibit tumor-selective targeting capabilities, demonstrating therapeutic potential against cancer cells. For example, single-atom catalysts have been investigated for application in nanocatalytic tumor therapy, leveraging distinct properties to induce oxidative stress and promote cell death in cancer cells. In addition, the exploration of copper-oxygen complexes within copper-containing enzymes as potential therapeutic targets remains a vibrant area of research45. Therefore, it is important to understand the functions and regulation of these transporters to develop strategies aimed at controlling cellular copper levels in cancer.

Cuproptosis

The earliest report of copper ion-induced cell death can be traced back to 19806. However, a clear mechanistic explanation for this phenomenon was lacking, leading to prolonged debate regarding copper ion-induced cell death. It was not until 2022 that Tsvetkov et al. introduced the concept of “cuproptosis” and provided a detailed elucidation of the underlying mechanism of copper-induced cell death (Figure 3)1. Cuproptosis is a form of regulated cell death initiated by intracellular copper accumulation. Copper import occurs primarily via the transporter, SLC31A1, which mediates Cu+ uptake, or through copper ionophores, such as ES and disulfiram (DSF), which facilitate Cu2+ entry. Copper binds to lipoylated components of the mitochondrial tricarboxylic acid cycle within the cell, particularly DLAT, prompting oligomerization and resulting in proteotoxic stress. The reductase, FDX1, has a dual role: reducing Cu2+ to Cu+ and contributing to DLAT lipoylation. In addition, copper impedes the FDX1-dependent biosynthesis of iron–sulfur (Fe–S) clusters. The combined effects of DLAT aggregation and disruption of Fe–S cluster biogenesis ultimately induce cell death. This process can be suppressed by copper chelators, such as GSH and tetrathiomolybdate, which sequester copper ions and reduce intracellular copper bioavailability. It has been shown that cuproptosis is distinct from other known forms of programmed cell death. First, the copper ion-binding compound ES does not induce activation of caspase 3/7, key markers of apoptosis. Furthermore, the cytotoxic effect of ES is unaffected when key apoptotic genes, BCL2 Associated X Protein (BAX) and BCL2-antagonist/killer 1(BAK1), are genetically deleted or when apoptosis and pyroptosis are pharmacologically inhibited using Benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK) and Boc-Asp(OMe)-fluoromethylketone (Boc D-FMK), respectively. These findings suggest that cuproptosis is mechanistically distinct from apoptosis. Similarly, other established cell death inhibitors, such as ferrostatin-1 (Fer-1), which inhibits ferroptosis, necrostatin-1 (Nec-1), which blocks necrosis, and N-acetylcysteine, which mitigates oxidative stress, did not attenuate cuproptosis, further supporting the unique molecular basis. Only the copper ion chelator, tetrathiomolybdate (TTM), has the capability to inhibit cuproptosis and restore cellular activity, suggesting that this form of cell death is mediated through a unique mechanism that is distinct from the currently established cell death pathways.

Figure 3
Figure 3

Schematic diagram of the mechanism underlying cuproptosis. This figure illustrates the molecular mechanism underlying cuproptosis, a copper-induced form of cell death. Copper ions (Cu2+) enter cells through copper ionophores, such as ES and DSF. ① Copper binds lipoylated DLAT (the substrate for lipoylation modification is LA) inside the mitochondria, leading to aggregation and subsequent proteotoxic stress. ② The copper also interacts with FDX1, reducing Cu2+ to Cu+ and promoting DLAT lipoylation. ③ However, copper inhibits the synthesis of Fe–S clusters by FDX1, disrupting cellular function. ④ This inhibition, in combination with DLAT aggregation, triggers a toxic response that culminates in cuprotosis. ⑤ The process of cuproptosis can be mitigated by the binding of copper ions to molecules, like GSH and TTM, which reduce the free copper ion concentration, thereby preventing DLAT aggregation and inhibiting cell death. DLAT, dihydrolipoamide S-acetyltransferase; DSF, disulfiram; ES, elesclomol; FDX1, ferredoxin 1; Fe-S, iron-sulfur cluster; GSH, glutathione; LA, lipoic acid; TTM, tetrathiomolybdate.

Therapeutic targeting of cuproptosis in cancer

Copper-related anti-cancer drugs have become a significant focus in current cancer research. Therapeutic strategies targeting copper in cancer treatment include the use of copper ion chelators to reduce copper bioavailability or the application of copper ion carriers or copper-containing drugs based on the principle of “cuproptosis” to increase intracellular copper levels in cancer cells (Figure 4). Chelators (e.g., TTM) deplete bioavailable copper to suppress angiogenesis and metastasis, while ionophores (e.g., ES) deliver copper into cells to induce cuproptosis or ferroptosis (Table 1). Nanotechnology platforms further enhance specificity. Copper-based nanoparticles exploit cancer-selective copper accumulation to synergize cuproptosis with ROS generation or immunomodulation (Table 2).

Figure 4
Figure 4

Cproptosis-targeted strategies for cancer therapy. This figure illustrates two targeted therapeutic strategies for inducing cuproptosis in cancer cells. (A) The copper ion carrier, ES, promotes cuproptosis in cancer cells by facilitating the accumulation of copper ions (Cu2+), especially in cells with high expression of lipoylated mitochondrial enzymes, such as DLAT. The aggregation of DLAT due to copper binding induces proteotoxic stress, leading to cuproptosis. (B) The combination of DSF, a copper ionophore, with copper agents targets cancer cells that exhibit high levels of ALDH expression. This combination strategy enhances the targeting specificity and therapeutic efficacy by promoting cuproptosis in ALDH-positive cancer cells, resulting in a more precise and effective treatment. ALDH, aldehyde dehydrogenase; DLAT, dihydrolipoamide S-acetyltransferase; DSF, disulfiram; ES, elesclomol.

View this table:
Table 2

Representative review of the application of Cupr-based nanoparticles in cancer therapy

Future directions of copper ions in cancer metabolism research

Prospects of copper metabolism-targeted precision medicine in cancer therapy

Copper metabolism-targeted precision medicine is promising for anti-cancer treatment. Copper metabolism has emerged as a novel biomarker for molecular imaging and targeted therapy in hepatocellular carcinoma (HCC). The elevated accumulation of copper ions in HCC and other cancers indicates that copper modulation therapy, such as the application of copper chelators and short-interfering RNAs specific to CTR1, inhibit tumor growth by disrupting excessive copper uptake. Moreover, copper metabolism represents a promising target for radionuclide therapy utilizing therapeutic copper radionuclides, underscoring the dual potential as a theranostic biomarker for the imaging and treatment of HCC46.

Advances in the fields of genomics, transcriptomics, and metabolomics have significantly enhanced our understanding of the complex metabolic alterations that occur in cancer cells, particularly the alterations related to copper metabolism. These omics technologies provide a comprehensive view of the molecular and cellular changes that underpin cancer development and progression. By integrating data from these diverse fields, researchers can identify specific metabolic pathways that are altered in cancer cells, offering potential targets for therapeutic intervention. Metabolomics has a crucial role in elucidating the metabolic reprogramming of cancer cells. This field focuses on the global analysis of small molecule metabolites, which can reveal critical information about the cancer state that might not be apparent through other methods. For example, metabolomics has been instrumental in identifying how cancer cells adapt metabolism to support rapid growth and survival, often under nutrient-poor conditions. This includes alterations in pathways, such as glycolysis, oxidative phosphorylation, and lipid metabolism, which are crucial for cancer cell proliferation and survival47,48. Furthermore, the integration of metabolomics with other omics technologies, such as genomics and transcriptomics, allows for a more detailed understanding of the molecular mechanisms driving cancer. This holistic approach can uncover novel metabolic vulnerabilities that could be exploited for cancer therapy. For example, the use of spatial metabolomics has provided insights into tumor-associated metabolic alterations, revealing potential metabolic vulnerabilities that might be targeted for therapeutic purposes49,50. In addition, application of metabolomics in cancer research has led to the discovery of specific metabolites and related enzymatic pathways directly associated with tumorigenesis. These findings underscore the importance of metabolites as building blocks of cellular structures and signaling molecules that can regulate cancer-related pathways51,52. In summary, the integration of genomics, transcriptomics, and metabolomics offers a powerful framework for understanding the metabolic alterations in cancer cells, including alterations related to copper metabolism. This integrated approach holds promise for identifying new therapeutic targets and developing more effective cancer treatments. Such information can be instrumental in developing personalized treatment plans that tailor the application of copper-based drugs, such as copper chelators [D-penicillamine (DP)] and TTM or copper ionophores (ES), to meet the specific needs of each patient (Table 2). Furthermore, precision medicine approaches may aid in minimizing the side effects of copper-based therapies by selectively targeting cancer cells with distinct copper-related vulnerabilities53,54.

Therapeutic strategies against hypoxic tumor microenvironment

Therapeutic approaches addressing oxygen-deprived tumor environments focus on multiple intervention mechanisms. Current research emphasizes pharmacologic agents that disrupt hypoxia-mediated signaling pathways, particularly pharmacologic agents focusing on HIFs that regulate tumor adaptation to low-oxygen conditions. HIF-1α has a multifaceted role in cancer cells under hypoxia7. HIF-1α suppresses DLAT expression, an essential enzyme of the tricarboxylic acid cycle that interferes with mitochondrial metabolism to change the sensitivity of tumor cell to copper-induced cell death. Moreover, HIF-1α induces MT2A to sequester mitochondrial Cu+, reducing labile Cu+ pools available for lipoyl-protein binding. This mechanism underlies the resistance of cancer cells to copper ion-based therapy under hypoxia. A comprehensive understanding of the interactions among HIF-1α, DLAT, and MT2A is essential for the development of more effective anti-cancer treatments in hypoxic tumor microenvironments. HIF-1α has a collaborative role in regulating mitochondrial metabolic reprogramming and metal homeostasis within tumor cells, leading to resistance against cuproptosis. HIF-1α upregulates genes associated with glycolysis under hypoxic conditions, while downregulating genes involved in mitochondrial oxidative phosphorylation, resulting in a metabolic shift within the cell. While copper chelation therapy has demonstrated clinical utility, the full therapeutic potential of copper modulation, particularly through cuproptosis induction, remains underexploited in oncology. In our preclinical study we confirmed that copper carriers, such as ES and CuCl2 (Cu), synergistically inhibit tumor growth in vivo. Nevertheless, increasing the ES + Cu doses raises safety concerns. The addition of an HIF-1α inhibitor holds promise for further enhancing the effectiveness and safety of ES + Cu in tumor treatment. However, one of the major limitations of this study involved the specificity of the orally active HIF-1α inhibitor (PX-478) for HIF-1α inhibition. The findings suggest that developing highly specific and effective HIF-1α inhibitors could sensitize cancer cells to cuproptosis, thus enabling cuproptosis as a promising approach for cancer therapy55.

Integration of metal homeostasis and tumor metabolism

Developing a therapeutic approach that integrates metal ion homeostasis with tumor metabolism is a promising future direction. Metal ions, like copper, iron, and zinc, have crucial roles in cellular functions, whose imbalance is linked to cancer56. By exploring the interactions between these ions and tumor metabolism, more comprehensive treatment strategies can be devised. For example, simultaneously targeting copper and iron metabolism may yield synergistic effects in cancer therapy. Because iron is vital for cancer cell growth, disrupting both iron and copper homeostasis could counteract the compensatory mechanisms used by cancer cells5.

The combination of copper ion modulation with other emerging cancer treatment modalities, such as immunotherapy and gene therapy, may result in more effective treatment outcomes. For example, copper-induced cuproptosis could potentially increase the immunogenicity of cancer cells, rendering cancer cells more vulnerable to immune-mediated destruction. In addition, gene therapy could be used to target genes involved in copper metabolism, thereby optimizing the effects of copper-based therapies. Ongoing research in this field is expected to reveal new and innovative approaches for incorporating copper ion modulation into cancer treatment.

Conclusions and future perspectives

The intricate relationship between copper homeostasis and tumor metabolism has emerged as a promising avenue for cancer therapy. This review has highlighted the dual role of copper ions in cancer biology: essential cofactors for cellular processes and inducers of cytotoxic effects through cuproptosis. The detailed elucidation of copper homeostasis mechanisms, including dietary absorption, systemic distribution, and intracellular utilization, underscores the importance of maintaining a delicate balance to prevent both copper deficiency and toxicity.

Recent advancements in copper-based nanotechnology and the identification of key transporters and enzymes involved in copper metabolism have opened new therapeutic avenues. Targeted delivery of copper to tumors, combined with the induction of cuproptosis, offers a novel approach to overcoming resistance mechanisms in cancer cells. However, the hypoxic tumor microenvironment remains a significant challenge because such an environment can upregulate copper-sequestering proteins and downregulate key mediators of cuproptosis.

Future directions in copper metabolism research should focus on integrating multi-omics approaches to identify novel therapeutic targets and elucidate the complex interactions between copper and other metabolic pathways. The development of combination therapies that target both copper homeostasis and hypoxia-induced resistance mechanisms holds promise for enhancing the efficacy of copper-based treatments. In addition, exploring the integration of copper ion modulation with emerging cancer treatment modalities, such as immunotherapy and gene therapy, may yield synergistic effects and improve patient outcomes.

In conclusion, the modulation of copper metabolism represents a powerful strategy for cancer therapy. By leveraging the unique mechanisms of cuproptosis and addressing the challenges posed by the tumor microenvironment, researchers can develop innovative approaches to target cancer cells more effectively. Further research in this area is essential to fully realize the potential of copper-targeted therapies in oncology.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Bing Yao, Zhou Yang.

Collected the references: Lixia Ju, Jun Xiang.

Figure preparation: Wei Su.

Wrote and revised the paper: Lili Niu.

  • Received April 18, 2025.
  • Accepted October 30, 2025.

References

  1. 1.↵
    2. Tsvetkov P,
    3. Coy S,
    4. Petrova B,
    5. Dreishpoon M,
    6. Verma A,
    7. Abdusamad M, et al.
    Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022; 375: 1254–61.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Gao J,
    3. Wu X,
    4. Huang S,
    5. Zhao Z,
    6. He W,
    7. Song M.
    Novel insights into anticancer mechanisms of elesclomol: more than a prooxidant drug. Redox Biol. 2023; 67: 102891.
  3. 3.↵
    2. Maung MT,
    3. Carlson A,
    4. Olea-Flores M,
    5. Elkhadragy L,
    6. Schachtschneider KM,
    7. Navarro-Tito N, et al.
    The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J. 2021; 35: e21810.
  4. 4.↵
    2. Lutsenko S,
    3. Roy S,
    4. Tsvetkov P.
    Mammalian copper homeostasis: physiological roles and molecular mechanisms. Physiol Rev. 2025; 105: 441–91.
    OpenUrlPubMed
  5. 5.↵
    2. Yang S,
    3. Song Y,
    4. Hu Y,
    5. Chen H,
    6. Yang D,
    7. Song X.
    Multifaceted roles of copper ions in anticancer nanomedicine. Adv Healthc Mater. 2023; 12: e2300410.
  6. 6.↵
    2. Hemani G,
    3. Tilling K,
    4. Davey Smith G.
    Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017; 13: e1007081.
  7. 7.↵
    2. Yang Z,
    3. Su W,
    4. Wei X,
    5. Pan Y,
    6. Xing M,
    7. Niu L, et al.
    Hypoxia inducible factor-1α drives cancer resistance to cuproptosis. Cancer Cell. 2025; 43: 937–54.e9.
    OpenUrlPubMed
  8. 8.↵
    2. Morrell A,
    3. Tallino S,
    4. Yu L,
    5. Burkhead JL.
    The role of insufficient copper in lipid synthesis and fatty-liver disease. IUBMB Life. 2017; 69: 263–70.
    OpenUrlCrossRefPubMed
  9. 9.↵
    2. de Romaña DL,
    3. Olivares M,
    4. Uauy R,
    5. Araya M.
    Risks and benefits of copper in light of new insights of copper homeostasis. J Trace Elem Med Biol. 2011; 25: 3–13.
    OpenUrlCrossRefPubMed
  10. 10.↵
    2. Kim V,
    3. Han MK,
    4. Vance GB,
    5. Make BJ,
    6. Newell JD,
    7. Hokanson JE, et al.
    The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest. 2011; 140: 626–33.
    OpenUrlCrossRefPubMed
  11. 11.↵
    2. Ohgami RS,
    3. Campagna DR,
    4. McDonald A,
    5. Fleming MD.
    The Steap proteins are metalloreductases. Blood. 2006; 108: 1388–94.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    2. Nose Y,
    3. Kim B-E,
    4. Thiele DJ.
    Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab. 2006; 4: 235–44.
    OpenUrlCrossRefPubMed
  13. 13.↵
    2. Dotan Y,
    3. So JY,
    4. Kim V.
    Chronic bronchitis: where are we now? Chronic Obstr Pulm Dis. 2019; 6: 178–92.
    OpenUrlPubMed
  14. 14.↵
    2. Öhrvik H,
    3. Nose Y,
    4. Wood LK,
    5. Kim B-E,
    6. Gleber S-C,
    7. Ralle M, et al.
    Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain. Proc Natl Acad Sci U S A. 2013; 110: E4279–E88.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    2. Lin C,
    3. Zhang Z,
    4. Wang T,
    5. Chen C,
    6. James Kang Y.
    Copper uptake by DMT1: a compensatory mechanism for CTR1 deficiency in human umbilical vein endothelial cells. Metallomics. 2015; 7: 1285–89.
    OpenUrlCrossRefPubMed
  16. 16.↵
    2. Kaler SG.
    ATP7A-related copper transport diseases—emerging concepts and future trends. Nat Rev Neurol. 2011; 7: 15–29.
    OpenUrlCrossRefPubMed
  17. 17.↵
    2. Lutsenko S.
    Dynamic and cell-specific transport networks for intracellular copper ions. J Cell Sci. 2021; 134: jcs240523.
  18. 18.↵
    2. Gromadzka G,
    3. Tarnacka B,
    4. Flaga A,
    5. Adamczyk A.
    Copper dyshomeostasis in neurodegenerative diseases—therapeutic implications. Int J Mol Sci. 2020; 21: 9259.
    OpenUrlCrossRefPubMed
  19. 19.↵
    2. Vašák M,
    3. Meloni G.
    Mammalian metallothionein-3: new functional and structural insights. Int J Mol Sci. 2017; 18: 1117.
    OpenUrlCrossRefPubMed
  20. 20.↵
    2. Chen L,
    3. Min J,
    4. Wang F.
    Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther. 2022; 7: 378.
    OpenUrlPubMed
  21. 21.↵
    2. Jiang Q,
    3. Zhao G,
    4. Song S,
    5. Chen Y.
    Analyzing the treatment of patients with acute exacerbation of COPD with the aid of intelligent diagnosis method. J Healthc Eng. 2022; 2022: 3962074.
  22. 22.↵
    2. Nývltová E,
    3. Dietz JV,
    4. Seravalli J,
    5. Khalimonchuk O,
    6. Barrientos A.
    Coordination of metal center biogenesis in human cytochrome c oxidase. Nat Commun. 2022; 13: 3615.
    OpenUrlCrossRefPubMed
  23. 23.↵
    2. Kilari D.
    Role of copper transporters in platinum resistance. World J Clin Oncol. 2016; 7: 106.
    OpenUrlPubMed
  24. 24.↵
    2. Horng Y-C,
    3. Cobine PA,
    4. Maxfield AB,
    5. Carr HS,
    6. Winge DR.
    Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11 in the assembly of yeast cytochrome c oxidase. J Biol Chem. 2004; 279: 35334–40.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    2. Love MI,
    3. Huber W,
    4. Anders S.
    Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15: 550.
    OpenUrlCrossRefPubMed
  26. 26.↵
    2. Leary SC,
    3. Kaufman BA,
    4. Pellecchia G,
    5. Guercin GH,
    6. Mattman A,
    7. Jaksch M, et al.
    Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. Hum Mol Genet. 2004; 13: 1839–48.
    OpenUrlCrossRefPubMed
  27. 27.↵
    2. Gu Z,
    3. Hübschmann D.
    Make Interactive Complex Heatmaps in R. Bioinformatics. 2022; 38: 1460–62.
    OpenUrlCrossRefPubMed
  28. 28.↵
    2. Palmgren MG,
    3. Nissen P.
    P-Type ATPases. Annu Rev Biophys. 2011; 40: 243–66.
    OpenUrlCrossRefPubMed
  29. 29.↵
    2. Itoh S,
    3. Kim HW,
    4. Nakagawa O,
    5. Ozumi K,
    6. Lessner SM,
    7. Aoki H, et al.
    Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation. J Biol Chem. 2008; 283: 9157–67.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    2. Pierson H,
    3. Muchenditsi A,
    4. Kim B-E,
    5. Ralle M,
    6. Zachos N,
    7. Huster D, et al.
    The function of ATPase copper transporter ATP7B in intestine. Gastroenterology. 2018; 154: 168–80.e5.
    OpenUrlPubMed
  31. 31.↵
    2. Linder MC.
    Copper homeostasis in mammals, with emphasis on secretion and excretion. A review. Int J Mol Sci. 2020; 21: 4932.
    OpenUrlPubMed
  32. 32.↵
    2. Polishchuk EV,
    3. Concilli M,
    4. Iacobacci S,
    5. Chesi G,
    6. Pastore N,
    7. Piccolo P, et al.
    Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Dev Cell. 2014; 29: 686–700.
    OpenUrlCrossRefPubMed
  33. 33.↵
    2. Li Q,
    3. Guan X,
    4. Wu P,
    5. Wang X,
    6. Zhou L,
    7. Tong Y, et al.
    Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020; 382: 1199–207.
    OpenUrlCrossRefPubMed
  34. 34.↵
    2. Skopp A,
    3. Boyd SD,
    4. Ullrich MS,
    5. Liu L,
    6. Winkler DD.
    Copper-zinc superoxide dismutase (Sod1) activation terminates interaction between its copper chaperone (Ccs) and the cytosolic metal-binding domain of the copper importer Ctr1. Biometals. 2019; 32: 695–705.
    OpenUrlPubMed
  35. 35.↵
    2. Bononi G,
    3. Masoni S,
    4. Di Bussolo V,
    5. Tuccinardi T,
    6. Granchi C,
    7. Minutolo F.
    Historical perspective of tumor glycolysis: a century with Otto Warburg. Semin Cancer Biol. 2022; 86: 325–33.
    OpenUrlCrossRef
  36. 36.↵
    2. Masoudi-Nejad A,
    3. Asgari Y.
    Metabolic cancer biology: structural-based analysis of cancer as a metabolic disease, new sights and opportunities for disease treatment. Semin Cancer Biol. 2015; 30: 21–9.
    OpenUrlCrossRefPubMed
  37. 37.↵
    2. Zhang C,
    3. Quinones A,
    4. Le A.
    Metabolic reservoir cycles in cancer. Semin Cancer Biol. 2022; 86: 180–88.
    OpenUrlCrossRefPubMed
  38. 38.↵
    2. Xue Q,
    3. Kang R,
    4. Klionsky DJ,
    5. Tang D,
    6. Liu J,
    7. Chen X.
    Copper metabolism in cell death and autophagy. Autophagy. 2023; 19: 2175–95.
    OpenUrlCrossRefPubMed
  39. 39.↵
    2. Zhu C,
    3. Li J,
    4. Sun W,
    5. Li D,
    6. Wang Y,
    7. Shen XC.
    Signaling mechanism of cuproptosis activating cGAS-STING immune pathway. JACS Au. 2024; 4: 3988–99.
    OpenUrlPubMed
  40. 40.↵
    2. Kuo MT,
    3. Fu S,
    4. Savaraj N,
    5. Chen HH.
    Role of the human high-affinity copper transporter in copper homeostasis regulation and cisplatin sensitivity in cancer chemotherapy. Cancer Res. 2012; 72: 4616–21.
    OpenUrlCrossRefPubMed
  41. 41.↵
    2. Li Y,
    3. Ma J,
    4. Wang R,
    5. Luo Y,
    6. Zheng S,
    7. Wang X.
    Zinc transporter 1 functions in copper uptake and cuproptosis. Cell Metab. 2024; 36: 2118–29.e6.
    OpenUrlPubMed
  42. 42.↵
    2. Lei G,
    3. Sun M,
    4. Cheng J,
    5. Ye R,
    6. Lu Z,
    7. Horbath A, et al.
    Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance. Cancer Cell. 2025; 43: 1076–92.e5.
    OpenUrlPubMed
  43. 43.↵
    2. Fucà G,
    3. Reppel L,
    4. Landoni E,
    5. Savoldo B,
    6. Dotti G.
    Enhancing chimeric antigen receptor T-cell efficacy in solid tumors. Clin Cancer Res. 2020; 26: 2444–51.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    2. Feng S,
    3. Aplin C,
    4. Nguyen TT,
    5. Milano SK,
    6. Cerione RA.
    Filament formation drives catalysis by glutaminase enzymes important in cancer progression. Nat Commun. 2024; 15: 1971.
    OpenUrlPubMed
  45. 45.↵
    2. Elwell CE,
    3. Gagnon NL,
    4. Neisen BD,
    5. Dhar D,
    6. Spaeth AD,
    7. Yee GM, et al.
    Copper–oxygen complexes revisited: structures, spectroscopy, and reactivity. Chem Rev. 2017; 117: 2059–107.
    OpenUrlPubMed
  46. 46.↵
    2. Wachsmann J,
    3. Peng F.
    Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma. World J Gastroenterol. 2016; 22: 221–31.
    OpenUrlPubMed
  47. 47.↵
    2. Schmidt DR,
    3. Patel R,
    4. Kirsch DG,
    5. Lewis CA,
    6. Vander Heiden MG,
    7. Locasale JW.
    Metabolomics in cancer research and emerging applications in clinical oncology. CA Cancer J Clin. 2021; 71: 333–58.
    OpenUrlCrossRefPubMed
  48. 48.↵
    2. Tufail M,
    3. Jiang CH,
    4. Li N.
    Altered metabolism in cancer: insights into energy pathways and therapeutic targets. Mol Cancer. 2024; 23: 203.
    OpenUrlCrossRefPubMed
  49. 49.↵
    2. Sun C,
    3. Li T,
    4. Song X,
    5. Huang L,
    6. Zang Q,
    7. Xu J, et al.
    Spatially resolved metabolomics to discover tumor-associated metabolic alterations. Proc Natl Acad Sci U S A. 2019; 116: 52–7.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    2. Chen WW,
    3. Pacold ME,
    4. Sabatini DM,
    5. Kanarek N.
    Technologies for decoding cancer metabolism with spatial resolution. Cold Spring Harb Perspect Med. 2024; 15: a041553.
  51. 51.↵
    2. Kwon H,
    3. Oh S,
    4. Jin X,
    5. An YJ,
    6. Park S.
    Cancer metabolomics in basic science perspective. Arch Pharm Res. 2015; 38: 372–80.
    OpenUrlPubMed
  52. 52.↵
    2. Wishart DS.
    Metabolomics for investigating physiological and pathophysiological processes. Physiol Rev. 2019; 99: 1819–75.
    OpenUrlCrossRefPubMed
  53. 53.↵
    2. Chrzan N,
    3. Hartman ML.
    Copper in melanoma: at the crossroad of protumorigenic and anticancer roles. Redox Biol. 2025; 81: 103552.
  54. 54.↵
    2. Michniewicz F,
    3. Saletta F,
    4. Rouaen JRC,
    5. Hewavisenti RV,
    6. Mercatelli D,
    7. Cirillo G, et al.
    Copper: an intracellular achilles’ heel allowing the targeting of epigenetics, kinase pathways, and cell metabolism in cancer therapeutics. ChemMedChem. 2021; 16: 2315–29.
    OpenUrlPubMed
  55. 55.↵
    2. Finley LW,
    3. Carracedo A,
    4. Lee J,
    5. Souza A,
    6. Egia A,
    7. Zhang J, et al.
    SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell. 2011; 19: 416–28.
    OpenUrlCrossRefPubMed
  56. 56.↵
    2. Chen L,
    3. Shen Q,
    4. Liu Y,
    5. Zhang Y,
    6. Sun L,
    7. Ma X, et al.
    Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases. Signal Transduct Target Ther. 2025; 10: 31.
    OpenUrlPubMed
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