Traditional cancer treatments, surgery, chemotherapy, and radiotherapy, often suffer from severe adverse effects and high drug resistance, leading to the therapeutic efficacy are less than satisfactory. [2] To overcome these "Achilles heel," minimally invasive or noninvasive treatment regimens are being introduced in cancer treatment to promote the production of specific toxic substances within tumor while sparing normal tissues from damage. [3] Among them, sonodynamic therapy (SDT), which uses low-intensity ultrasound (US) as an excitation source to trigger sonochemical reactions for generating highly cytotoxic reactive oxygen species (ROS), has been drawing increasing attention for its high tissue-penetration and safety to human body of ultrasonic waves. [4] Despite these unparalleled advantages, SDT is still in basic research stage and has not achieved widespread clinical application, because the deficiency of sonosensitizers and the specificity of tumor microenvironment (TME) substantially hinder the continuous production of ROS. [5] A variety of sonosensitizers with excellent performance have thus been proposed to overcome this conundrum during the past decades. [6] It is worth noting that the barriers to ROS generation are diverse, such as rapid recombination of sonoexcited electrons/ holes, inherent tumor hypoxia, and high levels of glutathione Conventional sonodynamic therapy is unavoidably limited by the tumor microenvironment, although many sonosensitizers have been developed to improve them to a certain extent. Given this, a concept of sonocatalytic hydrogen evolution is proposed, which is defined as an oxygen-independent therapeutics. To demonstrate the feasibility of the concept, the narrowbandgap semiconductor bismuth sulfide (Bi 2 S 3 ) is selected as the sonocatalyst and platinum (Pt) nanoparticles are grown in situ to optimize their catalytic performance. In this nanocatalytic system, the Pt nanoparticles help to capture sonoexcited electrons, whereas intratumoral overexpressed glutathione (GSH), as a natural hole sacrificial agent, can consume sonoexcited holes, which greatly improves the charge-separation efficiency and promotes controllable and sustainable H 2 generation. Even under hypoxic conditions, the Pt-Bi 2 S 3 nanoparticles can also produce sufficient H 2 under ultrasound irradiation. Mechanistically, mitochondrial dysfunction caused by H 2 and intratumoral redox homeostasis destruction by GSH depletion synergistically damage DNA to induce tumor cells apoptosis. At the same time, the Pt nanoparticles and holes can also trigger the decomposition of hydrogen peroxide into O 2 to relieve tumor hypoxia, thus being synergistic with GSH depletion to reverse tumor immunosuppressive microenvironment. The proposed sonocatalysis-mediated therapy will provide a new direction to realize facile and efficient cancer therapy.