Copper-Coordinated Covalent Organic Framework Produced a Robust Fenton-Like Effect Inducing Immunogenic Cell Death of Tumors

Increasing infiltration of CD8(+) T cells can enhance the response rate to immune checkpoint blockade (ICB) therapies. In contrast, immunogenic cell death (ICD) induced by intracellular reactive oxygen species (ROS) is an effective strategy to increase CD8(+) T cell infiltration. Cuproptosis is newly defined and reported by Tsvetkov et al. A Cu-coordinated covalent organic framework (COF) in which two valence states of copper ions are simultaneously loaded is prepared. On the one hand, Cu2+ undergoes a valence shift generating Cu+ which acts as an effective Fenton-like reagent to catalyze the production of (OH)-O-center dot and O-1(2) from cellular overexpressed H2O2, causing DNA damage and lipid peroxidation (LPO), which directly produce cytotoxicity. On the other hand, residual Cu2+ can effectively deplete endogenous cellular glutathione (GSH), converting it into glutathione disulfide (GSSG), further increasing intracellular oxidative stress and reducing the scavenging of ROS, thus further enhancing the Fenton-like effect and bringing toxic effects on tumor cells. The synergy of these two functions achieves ICD, helping for transforming cold tumor into hot tumor and efficient anti-tumor effects eventually. This work provides new insights into coordinated COF and inspire the development of more versatile COF for biomedical applications.

Automated summary

Increasing infiltration of CD8(+) T cells can enhance the response rate to immune checkpoint blockade therapies. In this study, cuproptosis, induced by a newly defined Cu-coordinated covalent organic framework (COF), was shown to effectively increase CD8(+) T cell infiltration. The COF exhibited two functions: Cu2+ acted as a Fenton-like reagent to generate cytotoxicity by catalyzing the production of reactive oxygen species (ROS), and residual Cu2+ depleted cellular glutathione to enhance intracellular oxidative stress, further enhancing the Fenton-like effect. The synergy of these two functions achieved immunogenic cell death and improved anti-tumor effects.