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Numerous therapeutic anti-tumor strategies have been developed in recent decades. However, their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors. Autophagy plays a key role in tumorigenesis and tumor treatment, in which the overproduction of reactive oxygen species (ROS) is recognized as the direct cause of protective autophagy. Only a few molecules have been employed as autophagy inhibitors in tumor therapy to reduce protective autophagy. Among them, hydroxychloroquine is the most commonly used autophagy inhibitor in clinics, but it is severely limited by its high therapeutic dose, significant toxicity, poor reversal efficacy, and nonspecific action. Herein, we demonstrate a reductive-damage strategy to enable tumor therapy by the inhibition of protective autophagy via the catalytic scavenging of ROS using porous nanorods of ceria (PN-CeO2) nanozymes as autophagy inhibitor. The antineoplastic effects of PN-CeO2 were mediated by its high reductive activity for intratumoral ROS degradation, thereby inhibiting protective autophagy and activating apoptosis by suppressing the activities of phosphatidylinositide 3-kinase/protein kinase B and p38 mitogen-activated protein kinase pathways in human cutaneous squamous cell carcinoma. Further investigation highlighted PN-CeO2 as a safe and efficient anti-tumor autophagy inhibitor. Overall, this study presents a reductive-damage strategy as a promising anti-tumor approach that catalytically inhibits autophagy and activates the intrinsic antioxidant pathways of tumor cells and also shows its potential for the therapy of other autophagy-related diseases.

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Publication history

Received: 27 July 2022
Revised: 27 September 2022
Accepted: 02 October 2022
Published: 22 November 2022

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© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

We thank Professor Yi Lv and his colleague from the National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research. This work was supported by grants from the National Natural Science Foundation of China (Nos. 81972938, 52002314, and 21872109) and partially supported by Funds of Shaanxi Province (Nos. 2021ZDLSF03-01, 2020TD-043, and TZ0124), General Project of Shaanxi Natural Science Basic Research Plan (No. 2021JM-589), and Xi’an People’s Hospital (Xi’an Fourth Hospital) Research Incubation Fund Project (LH-1). The authors also acknowledge the support from the Fundamental Research Funds for the Central Universities (Nos. D5000210829 and G2021KY05102).

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Email: nanores@tup.tsinghua.edu.cn

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