3 CONCLUSION AND PERSPECTIVES
​Cancer is already the second most lethal disease after cardiovascular disease, and this grave situation has led to the search for effective control and intervention techniques.50-52 Cuproptosis is a new form of PCD proposed in 2022 in which copper ions play an important role.29 Since then, the cellular regulatory mechanisms and signaling pathways involving cuproptosis have been investigated extensively, which propelled the movement toward cuproptosis inducers represented by copper-based nanomaterials for the eradication of malignant tumors. Copper-based nanomaterials can not only achieve targeted delivery of copper ions through surface modification, but also nicely circumvent the deficiencies of traditional cancer therapy, such as short blood circulation, poor solubility, low bioavailability, off-target effects, and nonspecific distribution.53,54 In this minireview, we first comprehensively expounded the regulatory mechanism of cuproptosis in the introduction section, and then introduced the application of cuproptosis mechanism in the field of nanomedicine, which may provide new insights into designing copper-based nanomaterials for cancer therapy.
Although the rapid development of studies on cuproptosis-based cancer therapy, challenges remain to be addressed, along with tremendous opportunities. Firstly, the understanding of the complicated molecular mechanism and associated regulatory pathways of cuproptosis are still in its infancy. Knowledge of the mechanism of cuproptosis may help in designing a more effective anti-cancer nanomaterial.15,55 Secondly, cuproptosis is a process closely related to cellular copper metabolism, so it is very important to reasonably control intracellular copper ion concentration in bothin vitro and in vivo studies. Regarding cancer, cuproptosis is a double-edged sword because it can not only kill cancer cells, but also induce copper toxicosis to destroy normal cells.56,57 Therefore, particular attention should be paid to the parameters such as type, dosage, timing, to obtain an optimal relationship between efficacy and side effects in practical application.58,59 Thirdly, copper-based nanomaterials might exert a cytotoxic effect via a cuproptosis-independent pathway. For example, copper ions may treat cancer through the Fenton reaction.60 Thus, a clear understanding of the action mechanism could aid the rational design of highly selective and specific copper-based nanosystems. Meanwhile, this also suggests that combining crosstalk between different cell death phenotypes may be an effective therapeutic regimen and possess potential clinical application in cancer treatment.61,62 Fourthly, the existing nanomaterials are weak in the responsive release of copper ions because of the small difference in enzyme activity or acidity between the tumor and normal tissue resulting from the diversity and heterogeneity of the tumor.7 Hence, there is a pressing demand for designing ultra-sensitive nanomaterials which can be activated within a very narrow threshold.63,64 Fifthly, during the circulation process, the dissolution of copper in copper-based nanomaterials seriously affects the therapeutic efficacy and cycle stability. Supramolecular nanomaterials exhibit strong stability due to their dynamic characteristics and high correlation constant between matching groups, and may be a promising cuproptosis inducer.65,66 Lastly, it is highly anticipated that cuproptosis can be extended to the treatment of other diseases. In addition to chemotherapy, nano-drug-based cell cuproptosis therapies are also expected to be widely combined with other treatments, which can further improve the treatment efficiency of tumor therapies based on cell cuproptosis.
In conclusion, with the deepening of our understanding in cuproptosis and its relationship with nanomaterials, cancer therapeutic outcome would be continuously improved through the design and development of copper-based nanomaterials.