Alkalinity and LSPR effect-based cuproptosis sensitizer to reverse tumor microenvironment for melanoma therapy

Cuproptosis is a promising therapeutic strategy for tumor, but its therapeutic efficacy is limited by the weak acidity and high concentration of glutathione (GSH) in the tumor microenvironment (TME). In this study, a novel alkalinity and localized surface plasmon resonance (LSPR) effect-based nanoreactor (MgO/Cu@C) is constructed to sensitise cuproptosis. Firstly, the alkalinity produced by MgO could reverse the acidic tumor microenvironment. Additionally, near-infrared (NIR) induced photothermal property and LSPR effect synergistic alkalinity can enhance GSH depletion of MgO/Cu@C. Thus, MgO/Cu@C+NIR sensitizes melanoma cells to cuproptosis by reversing TME. Furthermore, RNA sequencing transcriptome analysis confirms that MgO/Cu@C+NIR induces cuproptosis through copper overload-triggered lipoylated protein aggregation, inhibition of tumor metabolic pathways by alkalinity, NIR-drived HSP hyperactivation that depletes ATP reserves, and phosphatidylinositol signaling-mediated hijacking of survival pathways, which synergistically enforces irreversible metabolic collapse for melanoma cells. Meanwhile, MgO/Cu@C+NIR could inhibit bacterial infection and promote wound healing, thus addressing dual clinical applications for melanoma treatment and wound healing. Particularly, this study firstly reveals the mechanisms by which alkalinity and LSPR effect potentiate GSH depletion, as well as that alkalinity could sensitise cuproptosis by reversing the acidic microenvironment of tumor. The study provides a promising perspective for potential melanoma treatment based on cuproptosis.