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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.
Zhang et al. (Wed,) studied this question.