Mutual Waxing and Waning—A Novel Nano‐Biocomposite Harnesses the Lactate Gradient to Enhance Cuproptosis and Anti‐Tumor Immunity

Modifying the lactate gradient in tumors can induce acidosis and improve the immunosuppressive microenvironment. However, the therapeutic benefit is offset by compensatory metabolic adaptations and the inability of small-molecule drugs to regulate the gradient throughout the tumor tissue. This study developed a novel nano-biocomposite (LOB@CDSH) that combines cuproptosis to damage mitochondria and cut off energy supply, thereby improving the therapeutic outcome of acidosis induction. Simultaneously, it utilizes the invasive and tumor-colonizing capabilities of engineered bacteria to efficiently reduce lactate levels within tumor tissues. The MCT4 inhibitor syrosingopine (Syro) was loaded into a reactive oxygen species-responsive copper-based metal-organic framework (Cu-DTA) and coated with hyaluronic acid (HA) to form Cu-DTA@Syro@HA (CDSH). Syro inhibits lactate efflux, leading to intracellular lactate accumulation and acidosis. This promotes mitochondrial metabolism and induces lactylation modification of methyltransferase-like 16 (METTL16), thereby upregulating the expression of ferredoxin 1 (FDX1) to enhance cuproptosis. Lactate oxidase (LOX)-engineered Escherichia coli BL21 (LOB) serves as a carrier to deliver CDSH to the tumor site, where it proliferates, disseminates, and continuously expresses LOX to deplete lactate in the tumor microenvironment, thereby alleviating lactate-mediated immunosuppression. The aforementioned nano-biocomposite provides a reciprocally modulating strategy for lactate metabolism, offering a novel approach for tumor immunotherapy.