Nrf2 silencing amplifies DNA photooxidative damage to activate the STING pathway for synergistic tumor immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Immunotherapy
• Nanotechnology

Background:

• Photodynamic therapy (PDT) efficacy is limited by tumor cells' antioxidant systems, particularly the Nrf2 pathway and glutathione (GSH).
• Overcoming this antioxidant defense is crucial for enhancing PDT-induced immunogenic cell death (ICD) and antitumor immunity.

Purpose of the Study:

• To design a nanoadjuvant (RI@Z-P) that overcomes tumor cell antioxidant defenses by inhibiting Nrf2.
• To enhance PDT-mediated oxidative stress and activate STING-dependent immune responses.

Main Methods:

• Development of a versatile nanoadjuvant (RI@Z-P) incorporating Nrf2-specific small interfering RNA (siNrf2).
• Evaluation of RI@Z-P's ability to amplify photooxidative stress and induce DNA damage in tumor cells.
• Assessment of STING pathway activation, interferon-β (IFN-β) production, and immune cell responses (DC maturation, T-lymphocyte activation).

Main Results:

• RI@Z-P significantly amplified photooxidative stress and induced robust DNA oxidative damage.
• The nanoadjuvant activated the STING pathway, leading to increased IFN-β production.
• RI@Z-P demonstrated a potent adjuvant effect, promoting dendritic cell maturation, T-lymphocyte activation, and alleviating the immunosuppressive tumor microenvironment.

Conclusions:

• The RI@Z-P nanoadjuvant effectively enhances PDT by inhibiting the Nrf2 antioxidant system.
• This strategy boosts tumor immunogenicity and promotes a favorable immune response against cancer.
• RI@Z-P shows promise as an adjuvant for cancer immunotherapy.