Nanodrug Augmenting Antitumor Immunity for Enhanced TNBC Therapy via Pyroptosis and cGAS-STING Activation

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunology

Background:

• Pyroptosis, a programmed cell death, is suppressed in many cancers, hindering immune responses.
• GSDME is a key protein executed during pyroptosis.

Purpose of the Study:

• To develop a nanoliposome (GM@LR) for codelivering GSDME-expressing plasmid and manganese carbonyl (MnCO).
• To investigate the potential of GM@LR in treating triple-negative breast cancer (TNBC) through pyroptosis and immunotherapy.

Main Methods:

• Constructed GM@LR nanoliposomes for codelivery of GSDME plasmid and MnCO.
• Investigated MnCO's generation of Mn2+ and CO in the presence of H2O2.
• Analyzed CO-activated caspase-3 and GSDME cleavage to induce pyroptosis.
• Assessed Mn2+-mediated dendritic cell (DC) maturation via STING pathway activation.
• Evaluated GM@LR's efficacy in inhibiting tumor growth and promoting immune response.

Main Results:

• GM@LR successfully delivered GSDME plasmid and MnCO into TNBC cells.
• CO activated caspase-3, leading to GSDME cleavage and pyroptosis in 4T1 cells.
• Mn2+ promoted DC maturation through STING activation, increasing cytotoxic lymphocyte infiltration.
• GM@LR demonstrated effective tumor growth inhibition via combined pyroptosis and immunotherapy.
• Mn2+ showed potential for MRI-guided metastasis detection.

Conclusions:

• GM@LR nanodrug effectively inhibits tumor growth by inducing pyroptosis and activating STING-mediated immunotherapy.
• The combination of pyroptosis and immunotherapy offers a promising strategy for TNBC treatment.
• GM@LR holds potential for MRI-guided cancer metastasis detection.