Nanozymes have great potential applications in tumor treatment due to their good stability, high biocompatibility, easy preparation and versatility. However, it remains a challenge to design highly active nanozymes with tumor cell targeting. Herein, three nanoceria structures (nanoceria-rod; nanoceria polyhedra, abbreviated as nanoceria-poly.; and nanoceria-cube) with different surface oxygen vacancy concentrations are designed. Among them, nanoceria-rod shows the highest enzyme activity and tumor cell toxicity because of its highest concentration of oxygen vacancies on the surface. Further study shows that nanoceria-rod can selectively enter tumor cells because nanoceria-rod with a suitable isoelectric point (IEP) remains positively charged in the acidic microenvironment of the tumor but negatively charged in the physiological microenvironment of normal cells. Nanoceria-rod distributes in lysosomes and phagosomes to produce reactive oxygen species (ROS) in tumor cells. Finally, the mitochondrial membrane potential (MMP) was reduced, which caused cell apoptosis. This study provides an interesting new tumor-targeting therapy method, which could also be extended to other drug nanocarriers and diagnostic imaging nanomaterials for tumors.