机构:[1]Department 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.四川省人民医院[2]TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, P. R. China.[3]Department of Urology, Deyang People’s Hospital, Deyang 618099, Sichuan, P. R. China
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-gamma 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.
基金:
National Natural Science Foundation of China [52372263, 12132004, 32471367, 32171395]; Sichuan Science and Technology Program [2022NSFSC0048]; Program for Innovative Fundamental Research Incubation [UESTCY03023206100226]
第一作者机构:[1]Department 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.
通讯作者:
通讯机构:[1]Department 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.[2]TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, P. R. China.[3]Department of Urology, Deyang People’s Hospital, Deyang 618099, Sichuan, P. R. China