Dual Metabolic Rewiring Amplifies Cellular Oxidation and Reverses Immunosuppression for Combating Orthotopic Triple‐Negative Breast Cancer

Abstract Abnormal glucose/lactate metabolism is one of the key hallmarks of a tumor. Leveraging the excessive metabolite lactate to generate reactive oxygen species (ROS) by lactate oxidase (LOx) has become an efficient method for cancer therapy. However, the hypoxic tumor microenvironment (TME) and ROS‐scavenging enzymes largely restrict the catalytic activity of LOx. Herein, we design an ROS generator composed of LOx‐encapsulated and 7‐ethyl‐10‐hydroxycamptothecin (SN‐38)‐ and tamoxifen (TAM)‐coloaded membrane fusion liposomes, which can directly release cargoes via fusion with cancer cell membranes. Through the glycolysis promotion and mitochondrial respiration inhibition by TAM, and the antioxidant enzyme downregulation by SN‐38, the generator not only spares oxygen and increases intracellular lactate for LOx catalysis to yield cytotoxic H 2 O 2 , but also avoids ROS removal, realizing triple‐amplified ROS production and effective cancer cell killing. In the TME of an orthotopic breast cancer model, the generator consumes lactate and produces immunostimulatory H 2 O 2 , thereby promoting the M1‐like polarization of tumor‐associated macrophages and suppressing regulatory T cells to remodel the immunosuppressive TME. Additionally, the generator inhibits angiogenesis and further cancer metastasis via hypoxia inducible factor‐1α (HIF‐1α) signaling blockage. Collectively, this work provides an inspirational example of using a glucose/lactate metabolism interference strategy to fight against orthotopic triple‐negative breast cancer.