ABSTRACT Reactive oxygen species (ROS)‐based treatment strategy, such as sonodynamic and chemodynamic therapy (SDT/CDT), are frequently constrained by the immunosuppressive tumor microenvironment (TME), characterized by hypoxia and high intracellular reductants. Herein, we report the utilization of mild NIR‐II photothermal effect as a central coordinator to couple multiple therapeutic modalities and overcome these barriers. To demonstrate this concept, we construct a multifunctional nanoplatform (C‐D‐CHPB) by anchoring NIR‐II‐responsive carbon dots (CDs) onto Cu‐doped hollow Prussian blue nanocubes (CHPB) and loading DOX into the cavity of CHPB. Rather than relying on direct high‐temperature ablation, mild NIR‐II photothermal effect (∼43°C) acts as a master coordinator to (i) accelerate nanozyme redox catalysis, amplifying CDT‐mediated ROS production while enhancing GSH‐ox‐like and CAT‐like activities to reprogram the TME; (ii) alleviate tumor hypoxia, thereby boosting SDT‐mediated ROS generation; and (iii) promote tumor‐specific degradation of C‐D‐CHPB, enabling tumor‐specific DOX release and deeper intratumoral penetration. Heterojunction formation between CDs and CHPB further strengthens photothermal conversion, sonodynamic, and multi‐enzyme activities through improved electron/energy transfer process, yielding the cascade amplification of ROS production, initiation of ICD, promotion of DC maturation, and activation of T cells. Finally, C‐D‐CHPB‐mediated mild hyperthermia and heterojunction construction co‐amplified sono‐immunotherapy achieves eradication of primary tumors and inhibition of distant tumors. Overall, this work establishes a mild NIR‐II‐programmed, heterojunction‐augmented synergistic strategy that integrates photothermal, sonodynamic, nanocatalytic, and chemotherapeutic to overcome TME barriers and elicit robust antitumor immune response.
Xue et al. (2026) studied this question.