A stimuli-responsive cuproptosis switch boosts persistent immunotherapy for tumor eradication.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Cuproptosis, a copper-dependent cell death, offers novel cancer treatment potential.
• Current cuproptosis inducers face challenges with nonspecific copper release and low tumor accumulation.
• Precise control over copper ion release is crucial for effective and safe in vivo cancer therapy.

Purpose of the Study:

• To design a stimuli-responsive 'cuproptosis switch' for cancer-specific cuproptosis induction.
• To enhance cuproptosis-targeted therapy efficacy by combining it with immune response activation.
• To investigate the mechanisms of cuproptosis sensitization and evaluate antitumor efficacy in vivo.

Main Methods:

• Development of a bilayer copper nanocapsule (Cu2O and Cu2-xSe shells) with pH-sensitive copper ion release.
• Encapsulation of MSA-2, a STING activating agonist, within the nanocapsule.
• Evaluation of cuproptosis sensitization mechanisms (ion transporter regulation, GSH depletion, mitochondrial permeability) induced by ultrasound (US) irradiation and MSA-2 release.
• Assessment of combined therapeutic effects on tumor elimination, immunogenic cell death, and cGAS-STING pathway activation in a mouse model.

Main Results:

• The nanocapsule demonstrated switch-like, pH-dependent Cu+ release at pH 6.8, enabling cancer-specific delivery.
• US irradiation and MSA-2 release synergistically sensitized cells to cuproptosis by modulating copper homeostasis and depleting GSH.
• The combined therapy induced tumor-specific cuproptosis, initiated immunogenic cell death, activated the cGAS-STING pathway, and led to complete tumor elimination in mice at low doses without observable side effects.

Conclusions:

• The developed US-sensitized cuproptosis switch provides a precise and effective platform for cancer therapy.
• This approach holds promise for eliminating primary tumors and abscopal metastatic foci, potentially leading to complete tumor eradication.
• The strategy highlights the potential of combining targeted cell death induction with immune system activation for durable antitumor responses.