An oxygen-generating nanoplatform remodels the immunosuppressive tumor microenvironment via synergistic lactate depletion and sonodynamic therapy.

Lactate is an immunosuppressive molecule that plays an important role in tumor progression. Regulating lactate metabolism to remodel the immunosuppressive microenvironment represents a promising strategy for cancer therapy. However, owing to the hypoxic nature of the tumor microenvironment and single intervention strategies, the effect of lactate oxidase for cancer therapy is not as expected. Therefore, we engineered a self-oxygen-generating nanoplatform by encapsulating lactate oxidase and manganese porphyrin within nanoliposomes (ML@Lip). Lactate depletion via lactate oxidase promoted the polarization of tumor-associated macrophages toward the M1 phenotype in the tumor microenvironment and modulated innate antitumor immunity. Manganese porphyrin-mediated sonodynamic therapy induced not only tumor cell apoptosis but also immunogenic cell death. The release of damage-associated molecular patterns promoted dendritic cell maturation and T-cell activation, leading to immune system activation and the initiation of adaptive immunity. Additionally, manganese catalyzed the decomposition of hydrogen peroxide (derived from lactate breakdown) to generate substantial oxygen. This process established a positive feedback loop via lactate depletion while amplifying sonodynamic therapeutic effects through enhanced oxygen production. Therefore, the strategy of combining lactate depletion-induced starvation therapy, sonodynamic therapy and self-circulating oxygen generation effectively remodeled the immunosuppressive tumor microenvironment and inhibited tumor growth, thereby providing novel insights into targeted lactate metabolism therapy.