Harnessing biomimetic nano-regulators for in situ photothermia and lactate regulation to amplify cuproptosis immunotherapy.

Abstract

Cuproptosis represents a promising avenue for cancer immunotherapy, yet its efficacy is limited by difficulties in achieving targeted mitochondrial copper ion accumulation and upregulating cells reliance on mitochondrial respiration. To address this, we develop a biomimetic copper-based nanoplatform (SCTDM) coated with macrophage-tumor cell hybrid membranes (HM) and co-loaded with the lactate modulator syrosingopine (Su3118) and the copper ionophore disulfiram (DSF). SCTDM integrates active tumor targeting, in situ photothermal therapy (PTT), and lactate metabolism modulation, synergistically enhancing cuproptosis and antitumor immunity. SCTDM releases copper ions and DSF to facilitate mitochondrial copper ions delivery and induce immunogenic cell death (ICD). In the high hydrogen sulfide (H₂S) tumor microenvironment (TME), copper ions further form photothermal copper sulfide complexes that enhance PTT efficacy and reactive oxygen species (ROS) generation, thereby augmenting cuproptosis. Notably, the liberated Su3118 selectively inhibits monocarboxylate transporters (MCT1/4), suppressing lactate efflux while simultaneously sensitizing cells to cuproptosis by disrupting glycolysis and restoring mitochondrial respiration. Collectively, the synergistic combination of PTT and lactate metabolism modulation serves to potentiate cuproptosis-induced immunogenic cell death. This cascade effect culminates in the reprogramming of the immunosuppressive TME and augments anti-tumor immunity for eradicating primary tumors and preventing recurrence.