Manganese Capture-and-Release Vesicles for Cancer Immunotherapy

Area of Science:

• Biotechnology and Nanomedicine
• Cancer Immunology
• Infectious Disease Mechanisms

Background:

• Manganese (Mn2+) is crucial for activating the stimulator of interferon genes (STING) pathway.
• Yersinia pseudotuberculosis uses the TssS micropeptide to sequester Mn2+, evading host immunity.
• Cancer cells often exhibit an immunosuppressive tumor microenvironment.

Purpose of the Study:

• To develop a novel nanoplatform, MnCARS, for cancer therapy by leveraging manganese and the STING pathway.
• To engineer outer membrane vesicles (OMVs) capable of capturing and releasing endogenous manganese ions within cancer cells.
• To enhance anti-tumor immunity and therapeutic efficacy by combining manganese delivery with STING pathway activation.

Main Methods:

• Engineered E. coli outer membrane vesicles (OMVs) displaying TssS for Mn2+ capture and a VHL-PROTAC for controlled release.
• Surface anchoring of STING agonist MSA-2 to synergize with released Mn2+.
• In vitro assays with dendritic cells and in vivo studies using CT26 tumor models and orthotopic pancreatic cancer models.

Main Results:

• MnCARS successfully enriched Mn2+ and triggered dendritic cell maturation in vitro.
• In vivo administration of MnCARS demonstrated significant inhibition of subcutaneous CT26 tumor growth.
• The nanoplatform improved survival rates in an orthotopic pancreatic cancer model, indicating potent antitumor immunity.

Conclusions:

• MnCARS represent a versatile nanoplatform that redirects endogenous manganese for cancer therapy by potentiating cGAS-STING activation.
• The system effectively reverses the immunosuppressive tumor microenvironment and elicits robust antitumor immunity.
• A modified version, MnCARP, demonstrated potential for tumor targeting and monitoring via MRI, highlighting the platform's imaging capabilities.