Spatiotemporal Targeting Randle Cycle and Immune Checkpoint for Potent Antitumor Therapy.

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.