The
tumor microenvironment (TME) featured by immunosuppression
and hypoxia is pivotal to cancer deterioration and metastasis. Thus,
regulating the TME to improve cancer cell ablation efficiency has
received extensive interest in oncotherapy. However, to reverse the
immunosuppression and alleviate hypoxia simultaneously in the TME
are major challenges for effective cancer therapy. Herein, a multifunctional
platform based on Au nanoparticles and a carbon dots modified hollow
black TiO2 nanosphere (HABT-C) with intrinsic cascade enzyme
mimetic activities is prepared for reversing immunosuppression and
alleviating hypoxia in the TME. The HABT-C NPs possess triple-enzyme
mimetic activity to act as self-cascade nanozymes, which produce sufficient
oxygen to alleviate hypoxia and generate abundant ROS. The theoretical
analysis demonstrates that black TiO2 facilitates absorption
of H2O and O2, separation of electron–holes,
and generation of ROS, consequently amplifying the sonodynamic therapy
(SDT) efficiency. Specifically, HABT-C exhibits favorable inhibition
of immunosuppressive mediator expression, along with infiltrating
of immune effector cells into the TME and reversing the immunosuppression
in the TME. As a result, HABT-C can effectively kill tumor cells via
eliciting immune infiltration, alleviating hypoxia, and improving
SDT efficiency. This cascade nanozyme-based platform (HABT-C@HA) will
provide a strategy for highly efficient SDT against cancer by modulation
of hypoxia and immunosuppression in the TME.