mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy

Area of Science:

• Immunology
• Oncology
• Nanomedicine

Background:

• Improving T-cell responsiveness is crucial for treating immunologically cold tumors.
• Current immunotherapies often fail to establish effective antitumor immunity.
• Gasdermin-mediated pyroptosis is an emerging mechanism in cancer immunotherapy, requiring N-terminal cleavage for activation.

Purpose of the Study:

• To develop a single-agent mRNA nanomedicine strategy to trigger pyroptosis and enhance antitumor immunity.
• To investigate the potential of mRNA/LNP-induced pyroptosis in overcoming the challenges of cold tumors.
• To evaluate the synergistic effect of this strategy with anti-PD-1 immunotherapy.

Main Methods:

• Utilized mRNA lipid nanoparticles (LNPs) encoding the N-terminus of gasdermin to induce pyroptosis.
• Tested the strategy in multiple female mouse models with immunologically cold tumors.
• Assessed the impact on tumor microenvironment, T-cell activity, and overall antitumor immunity.

Main Results:

• Pyroptosis-triggering mRNA/LNPs successfully converted cold tumors into hot tumors.
• A positive feedback loop was established, promoting robust antitumor immunity.
• The treatment sensitized tumors to anti-PD-1 immunotherapy, leading to significant tumor growth inhibition.
• Antitumor effects extended to distant, non-treated lesions.

Conclusions:

• Single-agent mRNA nanomedicine encoding gasdermin N-terminus is a viable strategy for inducing pyroptosis and potent antitumor immunity.
• This approach effectively enhances immunotherapy responses in immunologically cold tumors.
• The strategy holds promise for improving therapeutic outcomes in challenging cancer types.