Autophagy-Targeting Fe-Cu Nanozyme for Tumor Immune Microenvironment Remodeling and Image-Guided Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• The tumor immune microenvironment (TIME) is crucial for tumor progression and therapy resistance.
• Autophagy in the TIME suppresses immune surveillance by reducing MHC-I expression, leading to immune escape.
• Current immunotherapies face limitations due to the suppressive TIME and immune evasion mechanisms.

Purpose of the Study:

• To develop a novel nanozyme-based strategy to modulate autophagy and restore anti-tumor immunity.
• To engineer iron-copper metal-organic frameworks (Fe-Cu MOFs) with potent redox activity for autophagy inhibition.
• To create a multifunctional nanoplatform for synergistic autophagy blockade and immune microenvironment reprogramming.

Main Methods:

• Engineered Fe-Cu MOFs with tunable nanozyme activities (peroxidase, glutathione peroxidase, oxidase-like).
• Identified an optimal Fe:Cu ratio for potent redox activity and autophagy inhibition.
• Developed a multifunctional nanoplatform (FCMP@CQ/PFH) by co-loading chloroquine (CQ) and perfluorohexane (PFH) into Fe-Cu MOFs.
• Utilized ultrasound for real-time visualization of therapeutic efficacy.

Main Results:

• Fe-Cu MOF nanozymes selectively impaired autophagy and restored MHC-I expression in tumor cells, enhancing immune recognition.
• The FCMP@CQ/PFH nanoplatform synergistically suppressed autophagy by combining nanozyme-driven redox stress and lysosomal inhibition.
• FCMP@CQ/PFH demonstrated enhanced cancer immunotherapy and suppressed metastasis in both in vitro and in vivo studies.
• Ultrasound imaging provided real-time monitoring of therapeutic outcomes.

Conclusions:

• The developed nanozyme-based strategy effectively inhibits autophagy and reprograms the tumor immune microenvironment.
• This dual-functional approach overcomes immune resistance and advances precision cancer immunotherapy.
• The combination of nanozyme therapy, autophagy inhibition, and immune modulation holds significant promise for cancer treatment.