Synergistical treatment of TNBC with nanogels via disrupting glycolysis, inducing ICD and ferroptosis

Abstract

Triple-negative breast cancer (TNBC) presents formidable therapeutic challenges due to its triple defense system including antioxidant capacity, glycolytic metabolism, and immunosuppressive microenvironment. To overcome these interconnected resistance mechanisms, we developed a multifunctional nanogel (3-in-1 NG) consisting of Fe²⁺-crosslinked boronate-conjugated mannose-alginate with encapsulated D-α-tocopheryl polyethylene glycol succinate (TPGS), which enables efficient tumor delivery. 3-in-1 NG achieved a 52.9% tumor growth inhibition rate and significantly impeded metastatic progression in 4T1 models. Mechanistically, the pH-triggered mannose release led to intracellular accumulation of mannose-6-phosphate. This effectively blocked glycolytic activity and reversed immunosuppressive lactate accumulation, priming tumors for ferroptosis. The nanoplatform simultaneously executes therapeutic functions including metabolic disruption via mannose-mediated glycolysis inhibition, TPGS-induced immunogenic cell death triggering dendritic cell maturation and cytotoxic T-cell infiltration, and Fe²⁺-dependent lipid peroxidation initiating ferroptosis cascade. These synergistic mechanisms established self-reinforcing therapeutic actions where metabolic inhibition enhanced both immune recognition and ferroptosis susceptibility, creating a feed-forward cycle that progressively dismantled tumor defenses. Our work pioneers a nanomedicine strategy that simultaneously exploits the metabolic plasticity, redox adaptability, and immune escape of TNBC, providing a unified synergistic solution for refractory malignancies.