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Endogenous/exogenous dual-responsive nanozyme for photothermally enhanced ferroptosis-immune reciprocal synergistic
Hanxi Zhang1, Jiazhen Lv1, Hao Wu2
1Department of Oncology & Cancer Institute, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, P. R. China.
Abstract:
Apoptosis resistance and immune evasion of tumor cells substantially increase the risk of cancer treatment failure. Here, a multifunctional nanozyme MET-CMS@FeTA (MCMSFT) formulated to induce nonapoptotic ferroptosis and boost immune recognition/attack, where compensatory mechanisms collectively overcome intrinsic tumor therapeutic limitations and improve medical intervention outcomes. Leveraging the multienzyme-like activity of MCMSFT to achieve oxygen generation, hydroxyl radical production, and glutathione depletion promotes hypoxia relief and triggers apoptosis/ferroptosis. Notably, MCMSFT-mediated photothermal therapy (PTT) facilitates direct tumor thermal ablation and offers exogenous heat to accelerate nanocatalytic reactions. Furthermore, PTT/ferroptosis-caused immunogenic cell death favors antitumor immunity initiation. Simultaneously, metformin administration and hypoxia amelioration down-regulate programmed death ligand 1 alleviating immune evasion. Interferon-γ secretion poses positive feedback to ferroptosis, thereby establishing a ferroptosis-immune mutual amplification loop. Antitumor performances illustrate that MCMSFT eliminates primary tumors and suppresses metastasis/rechallenge tumors. Collectively, MCMSFT surmounts the predicament of apoptosis resistance and immune evasion in cancer treatment to acquire more effective and comprehensive therapy efficacy.
Insights
This study introduces a novel nanozyme, MET-CMS@FeTA (MCMSFT), to combat cancer treatment failure by inducing ferroptosis and enhancing immune response. MCMSFT overcomes apoptosis resistance and immune evasion, leading to significant tumor elimination and improved therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Tumor cells often develop resistance to apoptosis and evade the immune system, leading to cancer treatment failure.
- Existing therapies struggle to overcome these intrinsic tumor limitations, necessitating novel therapeutic strategies.
Purpose of the Study:
- To develop a multifunctional nanozyme, MET-CMS@FeTA (MCMSFT), capable of inducing nonapoptotic ferroptosis and enhancing anti-tumor immunity.
- To investigate the combined effects of ferroptosis induction, photothermal therapy, and immune modulation for comprehensive cancer treatment.
Main Methods:
- Formulation of MCMSFT with multi-enzyme-like activity for oxygen generation, hydroxyl radical production, and glutathione depletion.
- Application of MCMSFT-mediated photothermal therapy (PTT) for tumor ablation and enhanced nanocatalysis.
- Administration of metformin and hypoxia amelioration to down-regulate programmed death ligand 1 and boost immune response.
Main Results:
- MCMSFT effectively relieved tumor hypoxia and triggered ferroptosis, overcoming apoptosis resistance.
- PTT combined with ferroptosis induced immunogenic cell death, initiating anti-tumor immunity.
- MCMSFT treatment led to the elimination of primary tumors and suppressed metastasis and tumor recurrence.
Conclusions:
- MCMSFT establishes a ferroptosis-immune mutual amplification loop, enhancing therapeutic efficacy.
- This nanozyme-based strategy effectively surmounts apoptosis resistance and immune evasion in cancer.
- MCMSFT offers a promising approach for more effective and comprehensive cancer therapy.
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