Highly Active Cu₁₄ Cluster Precisely Activates Autophagy Inhibitor to Amplify Cuproptosis Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Transition metal catalysts offer therapeutic potential but face challenges with non-essential metals and efficiency.
• Copper's biological role and the catalytic activity of copper clusters present an opportunity for targeted cancer therapy.

Purpose of the Study:

• To develop a novel copper cluster (Cu14) for synergistic induction of cuproptosis-associated immunogenic cell death (ICD) and autophagy suppression.
• To enhance cancer immunotherapy efficacy through a dual-action strategy utilizing a camouflaged copper cluster.

Main Methods:

• A Cu14 cluster was camouflaged with cancer cell membrane (Cu14@CM) for tumor targeting.
• Cu14@CM releases copper ions to induce cuproptosis via protein disruption.
• The cluster catalyzes reactions to produce autophagy inhibitors, blocking cytoprotective autophagy.

Main Results:

• Cu14@CM effectively triggered cuproptosis and released damage-associated molecular patterns (DAMPs), inducing ICD.
• Autophagy inhibition amplified DAMPs exposure, leading to increased dendritic cell maturation.
• Elevated tumor-infiltrating cytotoxic T lymphocytes were observed, reinforcing the antitumor immune response.

Conclusions:

• The Cu14 cluster-mediated strategy provides a dual-action approach for synergistic cuproptosis and autophagy suppression.
• This method shows significant potential for enhancing immunotherapy by amplifying anti-tumor immune responses.