Reactive oxygen species (ROS) as one kind of oxygen-dependent toxic free radical has been widely adopted in ROS-mediated therapies (RMT). However, two shackles, known as tumor hypoxia and high intratumor glutathione (GSH) levels, respectively, limit RMT as the former prevents ROS from generating, while the latter scavenges the ROS generated. Herein, we developed a novel nanoplatform to simultaneously overcome the two shackles by facile preparation of mesoporous carbon nanospheres (MCNs) with AIBI and raloxifene loaded inside as an initiator and inhibitor, respectively, and phase-change materials (PCMs) capped outside as gatekeepers. Upon 808 nm NIR light irradiation, the photothermal effect of MCNs melted PCMs causing the loaded AIBI and raloxifene to be released, during which the AIBI was further decomposed into oxygen-irrelevant radicals to kill cancer cells, while the raloxifene suppressed GSH synthesis, synergistically enabling an enhanced photonic thermodynamic cancer therapy.