Sorafenib, as a first-line drug for advanced hepatocellular carcinoma (HCC), could trigger ferroptosis by inhibiting cystine/glutamate transporter. However, low-level intracellular iron and insufficient activation of AMP-activated protein kinase (AMPK) confer impaired response to sorafenib. In this study, a unique sorafenib nanocomposite, dexterously modified with an iron motif (sora@Fe-MIL), was synthesized to escalate intracellular iron level and activate AMPK, further potentiating the ferroptotic effect of sorafenib. Remarkably, this strategic deployment of sora@Fe-MIL triggered an extensive demise of cancer cells, while manifesting negligible deleterious impact on normal cells. Two prominent ferroptosis biomarkers, Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), underwent pronounced downregulation, underscoring the efficacy of this strategy in inducing ferroptosis. Furthermore, the bioactivity of AMPK was considerably elevated, and its downstream targets were conspicuously inhibited by the treatment with sora@Fe-MIL. Using orthotopic HCC animal models, a substantial suppression of primary in situ tumor growth was observed and RNA sequencing elucidated an elevated degree of ferroptosis and AMPK activation with the treatment of sora@Fe-MIL. In conclusion, we proposed that the meticulously designed strategy for secure and efficacious iron-release and AMPK-activation could significantly potentiate the ferroptotic impact of sorafenib, thus resuscitating its therapeutic response in HCC patients.

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.