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AIM To investigate the antitumor effects and action mechanism of Zn-doped CuO nanocomposites (Zn-CuONPs). MATERIALS & METHODS Therapeutic effects and mechanisms of Zn-CuONPs were investigated both in vitro and in vivo. RESULTS Zn-CuONPs could inhibit tumor growth both in vitro and in vivo significantly. Zn-CuONPs treatment resulted in cytotoxicity, reactive oxygen species (ROS) production, DNA damage, apoptosis and autophagy. ROS scavenger N-acetylcysteine attenuated all of the above effects induced by Zn-CuONPs. N-acetylcysteine also restored the effects of Zn-CuONPs on protein expressions related to apoptosis, autophagy and NF-κB pathways. NF-κB pathway inhibitor pyrrolidine dithiocarbamate significantly attenuated Zn-CuONPs induced apoptosis and autophagy. CONCLUSION Our data demonstrated that Zn-CuONPs could inhibit tumor growth both in vitro and in vivo by ROS-dependent apoptosis and autophagy cross-linked by NF-κB pathways.