Nanosensitizer for Cancer Radioimmunotherapy via Anti-IL-35 Blockade Boosted Innate Immunity Activation

Area of Science:

• Immunology
• Biotechnology
• Nanomedicine

Background:

• The cGAS-STING pathway is a key target for cancer immunotherapy.
• STING agonists show dual effects, enhancing anti-tumor T cell activity but also promoting immune suppression via IL-35+ B regulatory (Breg) cells and reduced natural killer (NK) cell activity.

Purpose of the Study:

• To develop a tumor microenvironment-responsive nanosystem for controlled STING agonist release.
• To investigate the synergistic effects of the nanosystem with an anti-IL-35 blockade for enhanced cancer immunotherapy.

Main Methods:

• Development of a hollow mesoporous nanosystem releasing STING agonist MSA-2 and Mn ions in high glutathione environments.
• Utilizing the nanosystem for MRI-guided chemodynamic therapy and radiosensitization.
• Combining the nanosystem with anti-IL-35 blockade to modulate Breg and NK cell populations.

Main Results:

• The nanosystem effectively activated the cGAS-STING pathway by disrupting DNA.
• The combination therapy successfully mitigated Breg cell-mediated immunosuppression and restored NK cell activity.
• Significant enhancement of anti-tumor efficacy was observed.

Conclusions:

• The developed nanosystem offers a promising theranostic platform for cancer radioimmunotherapy.
• Targeting IL-35 is crucial for reversing immunosuppression and enhancing innate immune responses in cancer.
• This approach establishes a synergistic strategy for molecular imaging-guided cancer treatment.