Manganese Capture-and-Release Vesicles for Cancer Immunotherapy

Area of Science:

• Biotechnology
• Nanomedicine
• Immunotherapy

Background:

• Manganese activates the stimulator of interferon genes (STING) pathway.
• Yersinia pseudotuberculosis uses TssS micropeptide to sequester manganese, evading the immune system.
• Cancer cells often have 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) that capture and release endogenous manganese ions within cancer cells.
• To enhance antitumor immunity and potentially enable tumor imaging.

Main Methods:

• Engineered E. coli outer membrane vesicles (OMVs) displaying TssS for manganese capture.
• Incorporation of a von Hippel-Lindau (VHL) PROTAC motif for controlled manganese release.
• Surface anchoring of STING agonist MSA-2 to potentiate cGAS-STING activation.
• In vitro assays for manganese enrichment and dendritic cell maturation.
• In vivo studies in CT26 tumor models and orthotopic pancreatic cancer models.

Main Results:

• MnCARS successfully captured and released manganese ions in cancer cells.
• The system activated the cGAS-STING pathway, synergizing STING agonist and released manganese.
• MnCARS demonstrated in vitro dendritic cell maturation.
• In vivo, MnCARS inhibited tumor growth and improved survival in preclinical cancer models.
• A modified version, MnCARP, enabled MRI imaging of manganese release and STING activation.

Conclusions:

• MnCARS represents a versatile nanoplatform for cancer therapy by redirecting endogenous manganese.
• The system effectively activates antitumor immunity and reverses the immunosuppressive tumor microenvironment.
• The inherent imaging capabilities of the platform offer potential for theranostic applications.