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Regulating redox homeostasis in tumor cells and exploiting oxidative stress to damage tumors is an efficacious strategy for cancer therapy. However, the strengths of organic nanomaterials within this strategy are often ignored. In this work, a light-triggered reactive oxygen species (ROS) damaging nanoamplifier (IrP-T) was developed for enhanced photodynamic therapy (PDT). The IrP-T was fabricated with an amphiphilic iridium complex and a MTH1 inhibitor (TH287). Under green light stimulation, IrP-T catalyzed the oxygen in cells to generate ROS for realizing oxidative damage; meanwhile, TH287 increased the accumulation of 8-oxo-dGTP, further strengthening oxidative stress and inducing cell death. IrP-T could maximize the use of a small amount of oxygen, thus further boosting the efficacy of PDT in hypoxic tumors. The construction of nanocapsules provided a valuable therapeutic strategy for oxidative damage and synergizing PDT. [ABSTRACT FROM AUTHOR]

[Display omitted] • A fresh type of metal-sensitized sonocatalyst was designed. • The light/sono-responsive nanoplatform can generate adequate ROS and heat. • Generated ROS and heat mutualistically trigger immunogenic cell death. • The sonocatalyst activates immune response, hindering tumor growth and metastasis. Sonodynamic tumor therapy is limited by inefficient sonosensitizers and complex tumor microenvironments. Given this, a concept of metal-sensitized sonocatalyst is proposed and defined as a catalyst based on the metal sensitization effect of noble metals to advance semiconductor sonocatalytic activity. We load Au nanorods onto wide-bandgap semiconductor bismuth oxide to favor its sonocatalytic properties for supporting the concept's practicality. In the catalytic nano-system, Au nanorods improve the ability of bismuth oxide to separate electrons and holes under ultrasound, promoting multifarious reactive oxygen species (ROS) generation and enhancing the photothermal effect. Synergistically, bismuth oxide can consume intratumoral overexpressed glutathione, further disrupting the redox balance. Thus, ROS and heat can directly induce immunogenic cell death, reversing tumor immunosuppressive microenvironment in concert and promoting dendritic cell maturation and CD8+ T cell infiltration. The proposed metal-sensitized sonocatalyst will open up new avenues for sonocatalytic therapy. [ABSTRACT FROM AUTHOR]

• CuS nanosheet is a highly efficient ultrasound-controllable catalytic material. • Ultrasound-activated CO and ROS can trigger immunogenic cell death. • Oxygen generation relieves tumor hypoxia and reverses immunosuppression. Ultrasound-activated tumor catalytic therapy has great potential in clinical cancer treatment. However, the hypoxic and immunosuppressive tumor microenvironment impairs the efficacy of solid tumor treatment, leading to a high recurrence rate of metastatic cancer. Thus, reversing the tumor microenvironment remains a formidable challenge. To circumvent these critical issues, we employ ultrasound-activable carbon monoxide (CO) gas therapy and reactive oxygen species (ROS) production to trigger immunogenic cell death (ICD) and alleviate tumor hypoxia, achieving a combination of tumor therapy and reversal of immunosuppression to overcome the limitations of monotherapy and control tumor metastasis and recurrence. In brief, we first use copper sulfide (CuS) nanosheet as a highly efficient ultrasound-controllable catalytic nanomaterial, which can catalyze carbon dioxide, water, and oxygen to produce CO, oxygen, and ROS. Moreover, as a Fenton-like catalyst, it can catalyze hydrogen peroxide at tumor sites to generate ROS. The generated CO can attack mitochondria to accelerate their metabolism and produce more ROS, thus inducing ICD. In addition, the generation of oxygen can not only serve as the source of ROS, but it can also relieve tumor hypoxia and normalize the tumor immunosuppressive microenvironment. This results in the maturation of dendritic cells and the enhancement of T-lymphocyte recruitment and infiltration, further stimulating the antitumor immune response, mediating the regression of primary and distal tumors, and inhibiting lung metastasis. This in situ sono-activable catalytic therapy strategy minimizes the toxicity of CO and ROS leakage and provides a novel approach for designing new ICD inducers and improving therapeutic effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ce and S-doped Bi 2 O 3 nanosheets (BOSC) with oxygen defects are designed and synthesized. • Oxygen vacancies enhance the charge transfer and light absorption capacity. • Cascade conversion of reactive oxygen species is realized via band bending. • BOSC exhibits a variety of enzyme-like activities, leading to tumor oxidative stress amplification. • BOSC can initiate inflammatory programmed cell death, known as PANoptosis. Photocatalytic therapy (PCT) is a minimally invasive technique that utilizes reactive oxygen species (ROS) to selectively and optically impair tumor cells. However, the limited efficacy of photocatalysts hinders their more comprehensive application. In this study, we successfully synthesized Ce and S-doped Bi 2 O 3 (BOSC) nanosheets through topological synthesis. BOSC exhibits CAT-like and POD-like enzyme activities and can generate ROS and heat upon near-infrared light irradiation, thereby amplifying tumor oxidative stress. Introducing rare earth Ce element enhances light absorption, introduces oxygen vacancies, reduces bandgap, and facilitates charge separation. This Ce-doping also modifies the band position and Fermi level of BOSC, resulting in increased band bending at the solid–liquid interface, enabling a cascade reaction of ROS and enhancing ROS production. Additionally, BOSC demonstrates multiple enzyme activities by depleting GSH and catalyzing the production of ROS and O 2 from endogenous H 2 O 2 , thereby exacerbating cellular oxidative damage. The synergistic effect of BOSC post-illumination induces panoptosis, thereby improving the therapeutic efficacy against tumors. This strategy, involving the modulation of band structure and band bending through ion doping to introduce oxygen defects into the photosensitizer, provides a viable approach to enhance tumor phototherapy. [ABSTRACT FROM AUTHOR]