Cerium oxide (CeO x) with a reversible surface Ce3+/Ce4+ redox pair has played an important role in catalytic reactions, whereas catalase mimetics of CeO x have attracted little attention in the field of biotherapy. Herein, a smart photosensitizer-cerium oxide nanoprobe was developed to represent a promising paradigm in high-performance photodynamic therapy. The photosensitizer was linked to CeO x nanoparticles through a substrate peptide (EGPLGVRGK) of matrix metalloproteinase-2 (MMP-2). The smart nanoprobe could be converted from the "silent state" before arriving at the cancer cells to the "activated state" within the cells to turn on the fluorescence and 1O2 generation when the peptide linker (EGPLGVRGK) was cut by the cancer biomarker MMP-2. Moreover, CeO x played the role of an excellent catalase-like compound to decompose endogenous hydrogen peroxide to relieve tumor hypoxia. Via the conventional application of CeO x, our study showed innovatively how a smart nanoprobe could relieve tumor hypoxia and achieve a therapeutic effect for highly selective and efficient personalized treatment.