Genetically Edited Cascade Nanozymes for Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Immunology
• Nanotechnology

Background:

• Immune checkpoint blockade (ICB) shows promise in cancer therapy but is limited by poor dendritic cell (DC) activation and cytotoxic T lymphocyte (CTL) infiltration.
• Inducing immunogenic cell death (ICD) can enhance DC maturation and T-cell immunity, but solid tumors often exhibit low ICD levels, restricting durable antitumor efficacy.

Purpose of the Study:

• To develop a genetically edited nanozyme (gCM@MnAu) for enhanced cancer immunotherapy by inducing ICD and activating the stimulator of the interferon genes (STING) pathway.
• To investigate the synergistic effects of gCM@MnAu with ICB for improved antitumor responses.

Main Methods:

• A genetically edited cell membrane-coated cascade nanozyme (gCM@MnAu) was designed to generate hydroxyl radicals (•OH) in the tumor microenvironment (TME) for enhanced chemodynamic therapy (CDT) and ICD induction.
• Released Mn²⁺ ions were utilized to activate the STING pathway, promoting DC maturation.
• The efficacy of gCM@MnAu combined with PD-1/PD-L1 blockade was evaluated in breast cancer and lung metastasis mouse models.

Main Results:

• The gCM@MnAu nanozyme initiated a cascade reaction in the TME, producing •OH to boost CDT and ICD.
• The released Mn²⁺ activated the STING pathway, further enhancing DC maturation and T-cell priming.
• Combined therapy demonstrated synergistic effects, significantly improving antitumor responses and prolonging survival in mouse models.
• The nanozyme strategy effectively enhanced DC-mediated cross-priming against poorly immunogenic solid tumors.

Conclusions:

• Genetically edited nanozymes offer a promising strategy for cancer immunotherapy by overcoming limitations of current treatments.
• The developed gCM@MnAu nanozyme effectively induces ICD, activates the STING pathway, and synergizes with ICB to elicit potent systemic antitumor immunity.
• This approach holds potential for treating poorly immunogenic solid tumors and improving patient survival.