Lactate metabolism regulating nanosystem synergizes cuproptosis and ferroptosis to enhance cancer immunotherapy

Cuproptosis and ferroptosis exhibit superior synergistic advantages in antitumor therapy. While glutathione (GSH) has been identified as a key molecule in enhancing the synergistic effects of these two processes, inherent cellular redox homeostasis mechanisms limit its therapeutic efficacy. This inspired us to explore other new regulators to potentiate the synergistic effect. Through bioinformatics analysis and preliminary experimental validation, we discovered that lactate metabolism is closely associated with both ferroptosis and cuproptosis. Therefore, this work strategically targets lactate metabolism to synergistically activate cuproptosis and ferroptosis, and elucidate its immunotherapeutic mechanisms. For this purpose, we constructed a Syr-loaded nanodelivery system (Syr@mPDA@CP) using biocompatible mesoporous polydopamine (mPDA) as the carrier. Upon targeting tumor tissues, the released Syr significantly inhibits lactate efflux, leading to intracellular lactate accumulation. This lactate buildup further induces intracellular acidification, exerting dual effects: (1) promoting ferritin (FTH1) dissociation to release endogenous iron stores, thereby elevating intracellular iron levels; and (2) suppressing glycolysis and reducing ATP levels, which inactivates the copper export protein ATP7B. Combined with copper peroxide (CP)-derived Cu²⁺, these effects synergistically amplify intracellular copper accumulation. The elevated intracellular Cu and Fe concentrations subsequently induce dual cell death pathways of cuproptosis and ferroptosis, effectively enhancing cancer immunotherapy. This study pioneers a lactate metabolism-regulating strategy to synergistically amplify both ferroptosis and cuproptosis, offering novel perspectives for antitumor therapy.