Reductive damage induced autophagy inhibition for tumor therapy

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.

Supplementary material (cellular uptake of PN-CeO₂, effects of PN-CeO₂ on several common malignant tumor models, viability of HaCaT cells treated with PN-CeO₂ at different concentrations, time-dependent body-weight curves of SCL-1 tumor-bearing nude mice, the biodistribution of Ce element in main tissues and tumors after injection of PN-CeO₂, measurement of Ce element concentration in urine and feces samples, H&E-stained images of main organs, and measurement of liver and kidney function in mice after different treatment) is available in the online version of this article at 10.1007/s12274-022-5139-z.