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• Designing tumor microenvironment-responsive and sono-responsive two-dimensional heterojunction nanostructure. • Achieving chemoreactive and sonocatalytic cancer nanotherapy triggered by tumor microenvironment and ultrasound. • Superior performance of anti-tumor effect with high biosafety enabled by chemoreactive and sonocatalytic nanotherapy. Ultrasound (US)-activated sonodynamic therapy (SDT) has been extensively explored as an effective therapeutic modality for cancer treatment due to its noninvasiveness, physical targeting and deep tissue penetration. However, the inorganic semiconductor sonosensitizer-enabled SDT still suffers from the low therapeutic efficacy because of tumor hypoxia and low separation efficiency of electrons (e−) and holes (h+) from the energy-band structure of these inorganic sonosensitizers. Herein, the two-dimensional (2D) TiO 2 @MnO 2-x heterojunction nanostructure was rationally designed and engineered for simultaneously modulating the tumor hypoxic microenvironment and augmenting the therapeutic efficacy of SDT against tumor. The MnO 2-x component was heterogeneously grown onto the surface of initially synthesized 2D TiO 2 nanosheets (NSs), which not only acted as the catalysts for converting tumor-overexpressed hydrogen peroxide into oxygen and subsequently modulating the tumor hypoxia, but also catalyzed the Fenton reaction for the production of hydroxyl radicals. The heterojunction design of TiO 2 @MnO 2-x nanostructure effectively augmented the SDT efficacy of TiO 2 -based sonosensitizers under ultrasound activation by facilitating the separation of e−/h+ pairs. The simultaneously endowed tumor-hypoxia alleviation and synergistic sono/chemodynamic tumor nanotherapy achieved the high tumor cell-killing effect and tumor-suppression efficiency, as systematically demonstrated both in vitro and in vivo. This work provides a distinct paradigm of the heterojunction semiconductor nanostructure design for improving the ultrasound-based nanotherapy and achieving high tumor-treatment efficacy. [ABSTRACT FROM AUTHOR]