Sonodynamic therapy has exhibited tremendous merits such as deep tissue penetration, minimal invasiveness, and neglectable side effects, but the strong O2 dependence and complex tumor microenvironment limit the therapy efficiency. Herein, a type of BaTiO3@MnO2-based Z-scheme nano-heterojunction has been conjugated to doxorubicin-loaded carbon nanotubes to form functionalized hybrid nanocomposites for O2-independent and TME-modulating combinational tumor therapy. The existences of BaTiO3 and MnO2 afford a built-in microelectric field which induces band tilting to effectively transfer electrons with a Z-scheme track, prolonged the electron–hole separation lifetime, and maintained strong redox potentials for hydrolysis and abundant reactive oxygen species generation. The in vivo experiments prove that nano-heterojunctions actively accumulate at the tumor after intravenous injection and demonstrate a glutathione-responsive behavior to impair tumor anti-oxidant and enhance ROS contents. It was also noted that the ultrasound-mediated treatment in association with nano-heterojunctions showed a superior O2-independent tumor elimination (up to 90%) in company with dramatic recruitments of CD4+ and CD8+ T cells. Therefore, this study has validated the BaTiO3@MnO2-based Z-scheme nano-heterojunctions with tumor therapeutic interference in a drug-device-field integration manner and highlighted their promising utilities for modulating the tumor microenvironment and overcoming the O2 dependence for an efficacious tumor therapy in live animals.