A Bioinspired Immunostimulatory System for Inducing Powerful Antitumor Immune Function by Directly Causing Plasma...

Area of Science:

• Biomaterials Science
• Immunotherapy
• Cancer Research

Background:

• Gasdermin protein mediates pyroptosis and anti-tumor immunity, but cancer cells resist this via Gasdermin downregulation and membrane repair.
• Existing therapies face challenges in overcoming cancer cell resistance to pyroptosis.
• There is a need for artificial membrane disruptors (AMDs) to induce cell death and immune responses in pyroptosis-deficient cancers.

Purpose of the Study:

• To establish a micron-scale, Ce6-based artificial membrane disruptor (AMD) capable of inducing plasma membrane rupture (PMR) in gasdermin-deficient tumor cells.
• To evaluate the AMD's specificity, efficiency, and ability to induce programmed cell death and anti-tumor immune responses in vitro and in vivo.
• To explore the potential of AMDs in preclinical and clinical anti-tumor immunotherapy.

Main Methods:

• Development of micron-scale Ce6-based AMDs for targeted plasma membrane localization.
• Assessment of AMD-induced PMR under 660 nm red light, comparing its efficiency to free Ce6.
• In vitro and in vivo studies in gasdermin-deficient tumor models, including combination therapy with anti-PD-1, to evaluate tumor elimination and immune response.

Main Results:

• Micron-scale AMDs specifically localized Ce6 to the plasma membrane, mediating fast and irreversible PMR under red light.
• AMDs induced programmed and lytic cell death catalytically, requiring significantly less Ce6 than free molecules for comparable cancer cell death.
• In vivo, AMDs demonstrated tumor targeting and penetration, leading to efficient tumor elimination with minimal organ damage when combined with anti-PD-1 therapy, correlating with PMR-mediated inflammation and T-cell responses.

Conclusions:

• The developed Ce6-based AMD effectively induces plasma membrane rupture and cell death in gasdermin-deficient cancer cells, offering a new strategy for pyroptosis-resistant tumors.
• AMDs provide a controllable, light-driven method for inducing anti-tumor immune responses and represent a valuable tool for studying PMR immunogenicity.
• This study offers insights into designing bioinspired membrane disruptors for PMR and advancing anti-tumor immunotherapy.