Designed tumor microenvironment-remodeling bispolyphenol nanoparticles combined with αPD-L1 for enhanced melanoma immunotherapy

The efficacy of αPD-L1, an immune checkpoint inhibitor, in the treatment of melanoma is limited by individual patient variations and tumor immunosuppressive cells. Consequently, current immunotherapy of melanoma is far from satisfactory. In this study, bispolyphenol nanoparticles (Phl-CaCO 3 @Lut-Cu NPs) were constructed by wrapping a luteolin-copper (Lut-Cu) network around the surface of phloretin-loaded calcium carbonate (Phl-CaCO 3 ) nanoparticles. Upon entering tumor cells, Phl-CaCO 3 @Lut-Cu nanoparticles efficiently released Cu 2+ , phloretin (Phl), and luteolin (Lut) due to the acid-responsive properties of calcium carbonate and the metal-phenolic network. The copper ions mediated cuproptosis by binding to dihydrolipoamide acetyltransferase and induced cellular immune responses by promoting release of damage-associated molecular patterns (DAMPs). In addition, Phl blocked glucose transport by inhibiting glucose transporter 1 activity, thereby disrupting the energy supply process in tumor cells. Simultaneously, Lut inhibited expression of hypoxia-inducible factor-1α, negatively regulating aerobic glycolysis. This study aimed to reshape the tumor microenvironment by exploring the synergistic effects of cuproptosis and dual glycolysis inhibition, enhancing the T cell-mediated immune response, and suppressing tumor cell growth when combined with αPD-L1. This study provides a new perspective and strategy for melanoma immunotherapy.