Enzymatically Switchable Pyroptosis-Inducing Polymer Conjugate to Coordinate Host Immune Responses in Cancer...

Area of Science:

• Biomedical Engineering
• Immunology
• Oncology

Background:

• Gasdermin-D-mediated pyroptosis is crucial for immunity and a potential cancer immunotherapy target.
• Controlling pyroptosis spatiotemporally in cancer treatment remains a significant challenge.

Purpose of the Study:

• To develop a novel polymer conjugate (EPIC) for precise, enzyme-activated pyroptosis induction in cancer cells.
• To evaluate EPIC's efficacy as a cancer immunotherapy agent, alone and in combination with anti-PD-1 therapy.

Main Methods:

• An Enzymatically switchable Pyroptosis-Inducing polymer Conjugate (EPIC) was designed to activate via Cathepsin B in cancer cells.
• EPIC induces chemiluminescence resonance energy transfer (CRET) leading to reactive oxygen species generation and lysosomal disruption.
• In vitro and in vivo studies assessed EPIC's ability to trigger pyroptosis, activate immune cells, and treat tumors in mice.

Main Results:

• EPIC selectively triggered pyroptosis in cancer cells, releasing damage-associated molecular patterns and cytokines.
• In tumor-bearing mice, EPIC promoted dendritic cell maturation and NK cell activity.
• Combination therapy with EPIC and anti-PD-1 antibody significantly enhanced anti-tumor immunity, leading to durable remission and complete tumor regression in over 50% of mice.

Conclusions:

• EPIC serves as a versatile nanoplatform for precise cancer immunotherapy.
• EPIC demonstrates significant potential for effective cancer treatment by inducing immunogenic cell death and enhancing anti-tumor immune responses.