Despite the promise of sonodynamic processes in cancer therapy, existing sonosensitizers often fail to regulate the generation of reactive oxygen species (ROS)a gainst tumors, potentially leading to off-target toxicity to normal tissues.W e report at ransformable core-shell nanosonosensitizer (TiO 2 @CaP) that reinvigorates ROSg eneration and dissolves its CaP shell to release Ca 2+ in an acidic tumor microenvironment (TME) under ultrasound activation. Thus,T iO 2 @CaP acts as as mart nanosonosensitizer that specifically induces mitochondrial dysfunction via overloading intracellular Ca 2+ ions to synergize with the sonodynamic process in the TME. TiO 2 @CaP substantially enhances immunogenic cell death, resulting in enhanced T-cell recruitment and infiltration into the immunogenic cold tumor (4T1). In conjunction with checkpointb lockade therapy( anti-PD 1), TiO 2 @CaP-mediated sonodynamic therapyelicits systemic antitumor immunity, leading to regression of non-treated distant tumors and inhibition of lung metastasis.T his work paves the way to development of "smart" TME-activatable sonosensitizers with temporospatial control over antitumor responses.

Despite the promise of sonodynamic processes in cancer therapy, existing sonosensitizers often fail to regulate the generation of reactive oxygen species (ROS)a gainst tumors, potentially leading to off-target toxicity to normal tissues.W e report at ransformable core-shell nanosonosensitizer (TiO 2 @CaP) that reinvigorates ROSg eneration and dissolves its CaP shell to release Ca 2+ in an acidic tumor microenvironment (TME) under ultrasound activation. Thus,T iO 2 @CaP acts as as mart nanosonosensitizer that specifically induces mitochondrial dysfunction via overloading intracellular Ca 2+ ions to synergize with the sonodynamic process in the TME. TiO 2 @CaP substantially enhances immunogenic cell death, resulting in enhanced T-cell recruitment and infiltration into the immunogenic cold tumor (4T1). In conjunction with checkpointb lockade therapy( anti-PD 1), TiO 2 @CaP-mediated sonodynamic therapyelicits systemic antitumor immunity, leading to regression of non-treated distant tumors and inhibition of lung metastasis.T his work paves the way to development of "smart" TME-activatable sonosensitizers with temporospatial control over antitumor responses.