Pyroptosis-Inducing Engineered Microparticles for Cancer Immunotherapy.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Pyroptosis, a form of programmed cell death, can overcome tumor immunosuppression.
• Clinical applications of pyroptosis are limited by targeted induction challenges and biosafety concerns.

Purpose of the Study:

• To investigate geldanamycin (GA) as an inducer of pyroptosis via caspase-3 interaction.
• To develop a novel therapeutic strategy combining targeted pyroptosis with immune checkpoint blockade for enhanced lung cancer immunotherapy.

Main Methods:

• Geldanamycin (GA) interaction with caspase-3 at R207 was studied.
• Biomimetic dual-targeting microparticles (MPs) functionalized with anti-PD-L1 and anti-SIRPα nanobodies were developed.
• Therapeutic efficacy was evaluated in murine cancer models.

Main Results:

• GA specifically interacted with caspase-3 at R207, inducing high-efficiency pyroptosis.
• High-dose GA showed antitumor effects but caused toxicity and resistance via PD-L1 and CD47.
• The developed MPs achieved complete tumor regression, reduced toxicity, and induced robust antitumor immunity.

Conclusions:

• GA is a potent pyroptosis inducer targeting caspase-3.
• Biomimetic MPs functionalized with anti-PD-L1 and anti-SIRPα nanobodies represent a promising combinatorial therapy for lung cancer.
• This strategy effectively synergizes targeted pyroptosis with dual immune checkpoint blockade.