Harnessing Cuproptosis: A Novel Nanomedicine Strategy for Triple-Negative Breast Cancer

Abstract

Cuproptosis, a recently identified form of cell death triggered by copper ions, offers a promising therapeutic strategy for Triple-negative breast cancer (TNBC). This review explores the potential of cuproptosis-based nanomedicine in targeting TNBC. By inducing copper-dependent cell death and modulating the tumor microenvironment, these nanomaterials can effectively inhibit tumor growth, metastasis, and recurrence. This review delves into the mechanisms of cuproptosis, the design and synthesis of cuproptosis-inducing nanomaterials, their impact on tumor microenvironment and cancer stem cells, and their preclinical and clinical potential. Overcoming challenges such as toxicity, targeted delivery, and drug resistance is crucial for translating cuproptosis-based nanomedicine into effective clinical therapies for TNBC

Introduction

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of hormone receptors (estrogen receptor, progesterone receptor) and human epidermal growth factor receptor 2 (HER2) amplification. This aggressive nature often leads to poor prognosis and limited therapeutic options. While significant advancements have been made in the treatment of other breast cancer subtypes, TNBC remains a major clinical challenge.

The Burden of Triple-Negative Breast Cancer (TNBC)

TNBC accounts for approximately 15-20% of all breast cancer cases. Due to its aggressive nature, TNBC patients often present with advanced-stage disease and have a higher risk of metastasis and recurrence. Current standard-of-care treatments, including chemotherapy, radiation therapy, and immunotherapy, have limited efficacy in TNBC, highlighting the urgent need for novel therapeutic strategies.

Limitations of Current Therapies for TNBC

Despite recent advances in cancer therapy, TNBC remains a significant clinical challenge. The lack of specific molecular targets and the intrinsic resistance of TNBC cells to conventional therapies contribute to poor patient outcomes. Chemotherapy remains the primary systemic treatment for TNBC, but it often leads to drug resistance and severe side effects. While immunotherapy has shown promise in certain types of cancer, its efficacy in TNBC is limited.

The Emergence of Cuproptosis as a Novel Therapeutic Strategy

Cuproptosis, a recently discovered form of cell death, is characterized by copper-dependent lipid peroxidation and ferroptosis-like cell death. This novel cell death pathway offers a promising therapeutic target for cancer. By inducing cuproptosis, cancer cells can be selectively eliminated, potentially overcoming drug resistance and improving patient outcomes.

In recent years, nanotechnology has emerged as a powerful tool for cancer therapy. Nanomaterials can be designed to deliver therapeutic agents directly to tumor cells, enhancing efficacy and reducing side effects. By combining nanotechnology with cuproptosis-inducing agents, researchers are developing innovative nanomedicines to target TNBC.

Literature Review

Cuproptosis: A Novel Cell Death Pathway

Cuproptosis, a recently discovered form of regulated cell death, is characterized by copper-dependent lipid peroxidation and ferroptosis-like cell death. This unique mechanism of cell death is triggered by the accumulation of copper ions within cells, leading to oxidative stress and mitochondrial dysfunction.

The Mechanism of Cuproptosis

• Copper Ion Accumulation: Increased intracellular copper ion levels, either through dysregulated copper metabolism or exogenous copper supplementation, can trigger cuproptosis.

• Lipid Peroxidation: Copper ions catalyze lipid peroxidation, leading to the formation of reactive oxygen species (ROS) and lipid peroxidation products.

• Mitochondrial Dysfunction: Lipid peroxidation damages mitochondrial membranes, leading to mitochondrial dysfunction and decreased ATP production.

• Cell Death: The combination of oxidative stress, mitochondrial dysfunction, and lipid peroxidation ultimately leads to cell death.

Cuproptosis Inducers and Their Role in Cancer Therapy

Several compounds have been identified as potential inducers of cuproptosis, including:

• Copper Ions: Direct supplementation of copper ions can trigger cuproptosis in cancer cells.

• Copper-Based Compounds: Compounds containing copper ions, such as copper complexes and copper nanoparticles, can induce cuproptosis.

• Other Compounds: Certain small molecules and natural compounds have been shown to induce cuproptosis by modulating copper metabolism or directly targeting the cuproptosis pathway.

By targeting the unique metabolic vulnerabilities of cancer cells, cuproptosis inducers offer a promising therapeutic strategy for cancer treatment.

Nanomedicine for Cancer Therapy

Challenges in Cancer Nanomedicine

While nanomedicine has shown great promise in cancer therapy, several challenges hinder its clinical translation:

1. Physiological Barriers: The complex biological environment of tumors, including the extracellular matrix, immune cells, and blood vessels, can impede the efficient delivery of nanomaterials to tumor cells.

2. Rapid Clearance from the Body: Nanomaterials can be rapidly cleared from the bloodstream by the reticuloendothelial system (RES), limiting their bioavailability and therapeutic efficacy.

3. Toxicity: Nanoparticles, if not designed carefully, can induce systemic toxicity, affecting healthy tissues.

4. Tumor Heterogeneity: The diverse genetic and phenotypic heterogeneity of tumors can limit the effectiveness of targeted therapies, including nanomedicine.

Strategies for Targeted Delivery of Therapeutics

To overcome these challenges, researchers have developed various strategies for targeted delivery of therapeutic agents:

1. Passive Targeting: This approach relies on the enhanced permeability and retention (EPR) effect, which allows nanoparticles to accumulate in tumor tissues due to leaky vasculature and impaired lymphatic drainage.

2. Active Targeting: This strategy involves functionalizing nanoparticles with ligands that specifically bind to receptors overexpressed on tumor cells, such as folate, transferrin, and peptides.

3. Stimuli-Responsive Nanocarriers: These nanocarriers can release their therapeutic payload in response to specific stimuli, such as changes in pH, temperature, or redox potential, leading to targeted drug release at the tumor site.

4. Combination Therapies: Combining nanomedicine with other therapeutic modalities, such as chemotherapy, radiation therapy, or immunotherapy, can enhance therapeutic efficacy and overcome drug resistance.

By addressing these challenges and leveraging advanced nanotechnology, researchers aim to develop more effective and targeted cancer therapies.

Cuproptosis-Based Nanomedicine for TNBC

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of hormone receptors (estrogen receptor, progesterone receptor) and human epidermal growth factor receptor 2 (HER2). Due to the lack of targeted therapies, conventional treatments like chemotherapy and radiation therapy often have limited efficacy and significant side effects. Therefore, there is an urgent need for novel therapeutic strategies to improve the prognosis of TNBC patients.  

Cuproptosis, a recently identified form of cell death triggered by copper ions, has emerged as a promising therapeutic target. By disrupting iron homeostasis and inducing lipid peroxidation, cuproptosis can selectively eliminate cancer cells. Nanomedicine, with its ability to deliver therapeutic agents precisely to tumor sites, has the potential to enhance the efficacy of cuproptosis-inducing agents and minimize systemic toxicity.

Cuproptosis-Based Nanomedicine for TNBC

1. Design and Synthesis of Cuproptosis-Inducing Nanomaterials:

• Copper-based nanomaterials: Copper nanoparticles, copper oxide nanoparticles, and copper sulfide nanoparticles have been explored as potential cuproptosis inducers. These nanomaterials can be designed to release copper ions in a controlled manner, targeting tumor cells.

• Copper-loaded nanocarriers: Copper ions can be encapsulated within various nanocarriers, such as liposomes, polymeric nanoparticles, and mesoporous silica nanoparticles. These nanocarriers can enhance the bioavailability of copper ions, improve cellular uptake, and reduce systemic toxicity.

• Copper-conjugated biomolecules: Copper ions can be conjugated with biomolecules, such as peptides, antibodies, or aptamers, to achieve targeted delivery to tumor cells. This approach can improve the selectivity of copper ion delivery and enhance therapeutic efficacy.

2. Mechanisms of Action of Cuproptosis-Based Nanomedicine in TNBC:

• Induction of Cuproptosis: Cuproptosis-based nanomedicine can induce copper ion accumulation in cancer cells, leading to oxidative stress, lipid peroxidation, and ultimately, cell death.

• Regulation of Iron Metabolism: Copper ions can interfere with iron metabolism in cancer cells, leading to iron deficiency and impaired cellular proliferation.

• Modulation of Tumor Microenvironment: Cuproptosis-based nanomedicine can target tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs), which play crucial roles in tumor growth and metastasis. By inducing cuproptosis in these cells, the tumor microenvironment can be reprogrammed to favor anti-tumor immunity.

• Elimination of Cancer Stem Cells: Cancer stem cells (CSCs) are a small population of cells within tumors that are resistant to conventional therapies and can initiate tumor recurrence. Cuproptosis-based nanomedicine can selectively target and eliminate CSCs, leading to improved therapeutic outcomes.

3. Impact on Tumor Microenvironment and Cancer Stem Cells:

• Tumor Microenvironment Modulation: Cuproptosis-based nanomedicine can modulate the tumor microenvironment by inhibiting angiogenesis, suppressing inflammation, and promoting immune cell infiltration. This can create a more favorable environment for anti-tumor immune responses.

• Targeting Cancer Stem Cells: By inducing cuproptosis, these nanomaterials can eliminate cancer stem cells, which are resistant to conventional therapies and can contribute to tumor recurrence.

• Synergistic Effects with Other Therapies: Cuproptosis-based nanomedicine can be combined with other therapeutic modalities, such as chemotherapy, radiation therapy, and immunotherapy, to enhance therapeutic efficacy and overcome drug resistance.

In conclusion, cuproptosis-based nanomedicine holds great promise as a novel therapeutic strategy for TNBC. By targeting multiple hallmarks of cancer, these nanomaterials can effectively inhibit tumor growth, metastasis, and recurrence. Further research is needed to optimize the design and delivery of cuproptosis-inducing nanomaterials and to evaluate their clinical efficacy in TNBC patients.

Discussion

Preclinical and Clinical Studies

Due to the lack of targeted therapies, patients with TNBC often have poor prognoses. In recent years, there has been increasing interest in novel therapeutic strategies, including targeting specific cell death pathways. Cuproptosis, a newly identified form of cell death induced by copper ions, has emerged as a promising target for cancer therapy. This review delves into the potential of cuproptosis-based nanomedicine in suppressing TNBC, with a focus on its impact on the tumor microenvironment and cancer stem cells.  

Preclinical and Clinical Studies

1. In Vitro Studies: Cellular Uptake, Cytotoxicity, and Apoptosis

Numerous in vitro studies have demonstrated the efficacy of cuproptosis-inducing nanomaterials in targeting TNBC cells. These nanomaterials, often engineered with copper ions or copper-containing compounds, are designed to be efficiently taken up by cancer cells through various mechanisms, including receptor-mediated endocytosis and passive diffusion.

Once internalized, these nanomaterials can induce copper ion release, leading to a cascade of cellular events that ultimately culminate in cuproptosis. Key cellular processes affected by cuproptosis include:

• Mitochondrial dysfunction: Disruption of mitochondrial membrane potential and oxidative stress.

• Iron homeostasis imbalance: Alteration of iron metabolism and increased oxidative stress.

• Protein ferroptosis: Induction of lipid peroxidation and ferroptotic cell death.

2. In Vivo Studies: Tumor Growth Inhibition and Metastasis Suppression

In vivo studies have shown promising results for cuproptosis-based nanomedicine in suppressing TNBC tumor growth and metastasis. These nanomaterials have been delivered systemically or locally to target primary tumors and metastatic sites.

• Tumor Growth Inhibition: Cuproptosis-inducing nanomaterials can effectively inhibit tumor growth by inducing cell death in cancer cells.

• Metastasis Suppression: These nanomaterials can target cancer stem cells, which are responsible for tumor initiation and metastasis. By eliminating these cells, the risk of recurrence and metastasis can be reduced.

• Tumor Microenvironment Modulation: Cuproptosis-based nanomaterials can also modulate the tumor microenvironment by inhibiting angiogenesis, reducing inflammation, and promoting immune cell infiltration.

3. Clinical Trials: Current Status and Future Directions

While significant progress has been made in preclinical studies, clinical trials exploring the therapeutic potential of cuproptosis-based nanomedicine in TNBC are still in their early stages. Challenges such as toxicity, biodistribution, and targeted delivery need to be addressed to translate these promising preclinical findings into clinical applications.

Future research directions may include:

• Developing novel nanomaterials: Designing nanomaterials with enhanced targeting capabilities and controlled drug release.

• Combining cuproptosis-based nanomedicine with other therapies: Exploring synergistic effects with conventional therapies, such as chemotherapy and immunotherapy.

• Overcoming drug resistance: Developing strategies to prevent the emergence of drug resistance in cancer cells.

• Improving patient outcomes: Conducting clinical trials to evaluate the safety and efficacy of cuproptosis-based nanomedicine in TNBC patients.

Cuproptosis-based nanomedicine represents a promising therapeutic strategy for TNBC. By targeting cancer stem cells and modulating the tumor microenvironment, these nanomaterials can effectively inhibit tumor growth and metastasis. However, further research is needed to optimize their design, delivery, and clinical application. With continued advancements in nanotechnology and a deeper understanding of cuproptosis, we may be able to develop more effective and targeted therapies for TNBC.

Conclusion

Cuproptosis, a recently identified form of cell death, has emerged as a promising therapeutic target for cancer. This review has highlighted the potential of cuproptosis-based nanomedicine in suppressing triple-negative breast cancer (TNBC). By inducing copper-dependent cell death, these nanomaterials can effectively target cancer cells, particularly cancer stem cells, and modulate the tumor microenvironment.

Preclinical studies have demonstrated the efficacy of cuproptosis-based nanomedicine in inhibiting tumor growth, inducing apoptosis, and suppressing metastasis. Moreover, these nanomaterials have shown a synergistic effect when combined with other therapeutic modalities, such as chemotherapy and immunotherapy.

Challenges and Future Perspectives

While cuproptosis-based nanomedicine holds great promise, several challenges must be addressed to translate this approach into clinical applications:

Toxicity and Side Effects

• Off-target toxicity: Ensuring selective delivery of the nanomedicine to tumor cells is crucial to minimize systemic toxicity.

• Immunogenicity: The potential immunogenicity of nanomaterials can limit their therapeutic efficacy and lead to adverse immune responses.

• Long-term toxicity: Evaluating the long-term safety profile of these nanomaterials is essential to assess their potential side effects.

Improving Targeted Delivery and Therapeutic Efficacy

• Tumor-specific targeting: Developing nanomaterials with enhanced tumor targeting capabilities can improve therapeutic efficacy and reduce off-target effects.

• Overcoming drug resistance: Strategies to overcome drug resistance, such as combination therapy and targeted drug delivery, should be explored.

• Enhancing cellular uptake: Optimizing the surface properties and size of nanomaterials can improve their cellular uptake and intracellular delivery.

Personalized Medicine and Combination Therapies

• Patient stratification: Identifying patients who may benefit most from cuproptosis-based therapy can help optimize treatment outcomes.

• Combination therapies: Combining cuproptosis-based nanomedicine with other therapeutic modalities, such as chemotherapy, immunotherapy, and radiation therapy, may enhance therapeutic efficacy and overcome resistance.

In conclusion, cuproptosis-based nanomedicine represents a promising therapeutic strategy for TNBC. By addressing the challenges and exploring innovative approaches, we can harness the full potential of this emerging field to improve patient outcomes.