ROS-based tumor therapy based on nanocatalytic medicine has recently been proposed for its tumor-specificity. However, a safe and highly efficient strategy towards getting high enough ROS to kill the hypoxic cancer cells is still a great challenge. Herein, we report a simple pH/H₂O₂-activatable, O₂-evolving, and ROS regulating doxorubicin (DOX) and indocyanine green (ICG) co-loading PEGylated polyaniline (PANI) coated CeOx@polyacrylic acid (PAA) nanoclusters for highly selective and optimized cancer combination treatment. It can selectively and greatly enhance intracellular O₂ and ROS levels in tumor region, which depends on two-step catalytic properties of nanoceria (Ce⁴⁺/Ce³⁺ = 3.46, neutral surface charge, mostly localize into the cytoplasm, pH 7.4–6.5, catalase-like catalytic agents convert to Ce⁴⁺/Ce³⁺ = 0.58, negative surface charge, mostly localize into the lysosomes, pH 5–4, oxidase-like catalytic agents, triggered by near infrared (NIR) laser irradiation). Furthermore, the protective effect of polyethylene glycol (PEG), PANI, and PAA ensure that the nanoceria can only play the role of catalase under the irradiation of NIR light arrived at the tumor area. Moreover, loading of nanoceria and ICG onto PANI greatly enhanced photo thermal effect of nanoparticles (NPs), which is useful for killing cancer cells by relieving hypoxia and promoting cross-membrane drug delivery to further enhance photodynamic therapy and chemotherapy efficiency. The chemo-photo combination therapies fantastically inhibited tumor growth and prevented tumor recurrence in vivo, suggesting a smart nanotheranostic system to achieve more precise and effective therapies in O₂-deprived tumor tissue.