Spatiotemporal Targeting Randle Cycle and Immune Checkpoint for Potent Antitumor Therapy

ABSTRACT Tumor metabolic reprogramming plays a crucial role in cancer progression and therapeutic resistance. The competitive and compensatory relationship between glucose and lipid metabolism—known as the Randle cycle—poses a major challenge to single‐pathway metabolic inhibition strategies. In this study, we developed a glucose oxidase‐based nanogel (GOX‐NG) system using catechol‐functionalized alginate, which exhibits enhanced tumor penetration, prolonged retention, and sustained glucose depletion in the tumor microenvironment. When combined with etomoxir (ETX), a fatty acid oxidation (FAO) inhibitor, this system effectively implements dual metabolic suppression, thereby enhancing reactive oxygen species (ROS)‐induced immunogenic cell death and reprogramming the tumor immune microenvironment. Further combination with the immune checkpoint inhibitor αPD‐1 amplified antitumor immune responses, achieving complete tumor regression in 60% of animals and full survival in 100% of tumor‐bearing mice. This strategy demonstrates significant potential in the treatment of metastatic tumors through a synergistic starvation–oxidation–immunotherapy loop and paves the way for applying intratumorally‐retaining nanogels to a broad spectrum of therapeutic proteins targeting metabolic pathways.