Immune checkpoint blockade (ICB) therapy has attracted widespread attention and would be amplified by the immunogenic cell death (ICD) of cancer cells. Here, inspired by the natural enzyme-reaction system (ERS) for reactive oxygen species (ROS) biocatalysis, we propose the de novo design of efficient and precise Ru-based redox centers on TiO2 (Ru/TiO2) with an ERS-simulated and tumor microenvironment (TME)-adaptive process to boost immunogenicity for cancer ICB therapy. Our studies demonstrate that the Ru/TiO2 has precisely engineered, partially lattice-confined, and electron-rich Ru sites for superior, pH-dependent, and simultaneous ROS production and oxygen (O2) evolution in the TME, which enables it to serve as a TME-adaptive ICD initiator for adjunctive augmentation of ICB potency while ameliorating an immunosuppressive TME, thereby synergistically suppressing solid and metastatic tumors. We suggest that the design of this ERS-inspired nanobiocatalyst will open up a promising pathway for engineering ROS-generating materials to reverse immunosuppression and enhance immunogenicity, thus transforming “immune-cold” tumors into “immune-hot” tumors.