Focusing on the dual role of cuproptosis in colitis and carcinogenesis: A novel perspective on immune regulation

Research Background

Cuproptosis represents a novel mechanism of cell death characterized by intracellular copper ion accumulation. Unlike other cell death pathways, its unique process has garnered significant interest due to its promising applications in treating inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence suggests that copper metabolism and cuproptosis may play a dual regulatory role in pathological cellular environments, particularly in modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. Appropriate copper levels can promote disease progression and exert synergistic effects, but beyond a certain threshold, copper may suppress disease development by inducing cuproptosis in pathological cells. This makes dysregulated copper levels a potential novel therapeutic target for IBD and CRC.

This article highlights the dual role of copper metabolism and cuproptosis in the progression of IBD and CRC while exploring the potential applications of copper-based therapies in disease treatment. Additionally, it further elucidates the regulatory effects of the tumor immune microenvironment on cuproptosis and establishes the therapeutic potential of cuproptosis-targeting strategies in overcoming resistance to conventional chemotherapy and emerging immunotherapies. This provides new research directions for the future development of cuproptosis inducers. Finally, the article discusses potential molecular targets of cuproptosis and the latest advances in related genes for treating IBD and CRC, while emphasizing future research priorities and unresolved questions.

Research Progress

1.Bidirectional Regulatory Role of Copper Metabolism and Cuproptosis in IBD and CRC
Studies have demonstrated that copper metabolism and cuproptosis exhibit dual effects in the pathological processes of IBD and CRC. As an essential trace element, copper homeostasis imbalance can lead to cell death, with cuproptosis representing a newly identified copper-dependent cell death mechanism.

In IBD, copper affects intestinal barrier function by regulating oxidative stress and immune responses. For example, excessive copper exacerbates oxidative stress and damages intestinal epithelial cells, while copper chelators can alleviate inflammation by inhibiting the NF-κB pathway. In CRC, copper accelerates disease progression by promoting angiogenesis and tumor metastasis, yet cuproptosis can selectively kill tumor cells. These findings reveal the complex role of copper metabolism and cuproptosis in intestinal diseases.

2.Interaction between cuproptosis and the tumor immune microenvironment
Cuproptosis not only directly induces tumor cell death but also remodels the tumor immune microenvironment (TME). Studies have found that copper complex nanoparticles (Cu(I)NPs) can induce cuproptosis and release damage-associated molecular patterns (DAMPs), promoting dendritic cell (DC) maturation and CD8+ T cell infiltration.

In addition, copper ionophores (e.g., disulfiram/copper complexes) enhance anti-tumor immune responses by promoting M1 macrophage polarization and suppressing PD-L1 expression. These findings demonstrate that cuproptosis can potentiate existing immunotherapies through immune modulation, offering novel strategies to overcome tumor resistance.

3.Clinical Potential of Copper-Targeted Therapies
Copper metabolism-related proteins (including ATP7A/B and FDX1) have emerged as potential therapeutic targets for CRC. Preclinical studies indicate that copper chelators (e.g., tetrathiomolybdate) and copper ionophores (e.g., disulfiram) can inhibit tumor growth by inducing cuproptosis.

Furthermore, copper-based nanomedicines (e.g., E-C@DOX NPs) combined with chemotherapy or photothermal therapy have significantly enhanced antitumor efficacy. In clinical trials, disulfiram/copper complexes have demonstrated good safety profiles in some patients, though their therapeutic effects require further validation. These advancements have laid the foundation for the clinical translation of copper-targeted therapies.

4.Synergistic Effects Between Cuproptosis and Other Cell Death Pathways
Cuproptosis exhibits crosstalk with other cell death mechanisms such as apoptosis and ferroptosis. For instance, disulfiram/copper complexes simultaneously trigger cuproptosis and ferroptosis by inhibiting PKM2-driven glycolysis and promoting Fe-S cluster protein degradation. Additionally, cuproptosis-induced immunogenic cell death (ICD) can enhance the efficacy of immune checkpoint inhibitors. These synergistic effects provide new insights for developing combination therapies, though precise regulation of copper homeostasis remains a challenge.

Future Research Directions and Challenges

As a newly identified mechanism of cellular demise, cuproptosis is undergoing rigorous investigation across diverse disciplines, including chemotherapy, TME regulation, immune-based therapies, and outcome prediction, to develop more effective cancer management strategies. However, the study of cuproptosis is still a nascent field, with current studies primarily focused on its correlation with IBD and CRC. Numerous underlying mechanisms remain to be elucidated, necessitating additional fundamental investigations. Future investigations should focus on deciphering the precise molecular pathways that govern Cu metabolism and cuproptosis in the context of IBD and CRC, as well as explore strategies to modulate Cu levels to maximize therapeutic efficacy. Despite its potential, several challenges remain in cuproptosis research, which also pose obstacles for clinical applications. First, the potential clinical applications and safety concerns related to cuproptosis modulation remain to be fully explored, posing significant challenges for the clinical translation of cuproptosis inducers. Both copper deficiency and excess can induce systemic toxicity, necessitating additional clinical studies to evaluate how copper level modulation affects prognosis in IBD and CRC patients. Such investigations are crucial for improving the targeting efficiency and in vivo stability of these therapeutic agents. Second, Cu’s potential as a therapeutic target needs further exploration. This includes developing therapies based on Cu metabolism and cuproptosis, such as gene knockouts and cell-based approaches, while research efforts are shifting toward novel copper inducers, including plant-derived compounds, synthetic molecules, and nanotechnology-based carriers, to improve targeted drug delivery to affected cells. Additionally, the connection between copper metabolism, cuproptosis, and the intestinal immune microenvironment requires further investigation. Combining cuproptosis with immunotherapy could offer a promising strategy to combat IBD and CRC, significantly improving treatment outcomes and extending patient survival. However, it remains unclear whether cuproptosis and its signaling pathways play a protumor role in tumor initiation and development. The current lack of validated cuproptosis biomarkers underscores the need for additional research to enable precision therapeutic interventions. Comprehending the interplay between cuproptosis and alternative forms of cellular demise constitutes another pivotal research domain. Investigating the connections between cuproptosis and other kind of pathways, including apoptosis, ferroptosis, and pyroptosis, may deepen our comprehension of Cu-related diseases and accelerate the progression of targeted therapies to induce tumor cell death more effectively. Looking forward, the discovery of specific biomarkers and personalized antitumor strategies will likely enable the clinical translation of therapies based on Cu metabolism and cuproptosis.

In summary, cuproptosis represents a potential novel therapeutic avenue for IBD and CRC. Advancing understanding of cuproptosis regulation and enhancing its induction efficiency position this pathway as a novel therapeutic strategy for disease intervention. This strategy has the potential not only to suppress disease onset and progression effectively but also to improve patient survival and quality of life through precision therapies. Therefore, understanding the involvement of cuproptosis in pathological processes and developing related treatment strategies holds substantial scientific and medical importance.

Sources: https://doi.org/10.34133/research.0698