Tumor-Microenvironment-Responsive Nanosystem for Enhanced Melanoma Immunotherapy via Dual Epigenetic Regulation and Cuproptosis

Abstract As a highly malignant tumor, melanoma is associated with poor prognosis and high recurrence rates. Despite advances in surgery, radiotherapy, chemotherapy, and immunotherapy, drug resistance and immune evasion remain major obstacles. Epigenetic dysregulationsuch as aberrant DNA methylation and histone deacetylationplays a pivotal role in melanoma progression by silencing tumor suppressor genes and promoting immune escape. Although epigenetic therapies have shown promise, single-target strategies often lead to limited efficacy and acquired resistance. Moreover, emerging evidence suggests that cuproptosis, a copper-triggered, mitochondria-dependent cell death modality, is an effective immunogenic mechanism that synergizes with epigenetic reprogramming. Here, we designed a tumor microenvironment-responsive nanosystem (SAHA-CaCO3@DMY-Cu), which can combine dual epigenetic modulation with cuproptosis to overcome tumor immunosuppression. This nanosystem can simultaneously deliver the histone deacetylation inhibitor vorinostat (SAHA) and the DNA methylation inhibitor dihydromyricetin (DMY) and release copper ions to trigger cuproptosis. This nanosystem achieved an 80.7% reduction in tumor growth and triggered a strong immune activation effect, significantly promoting the maturation of dendritic cells and the intratumoral infiltration of CD4+ and CD8+T cells while reducing Treg cells. Transcriptomics analysis confirmed the enrichment of immune-related pathways (for example, the cytokine−cytokine receptor interactions and the TNF signaling pathway) as well as ribosome generation, thereby verifying the dual epigenetic regulation−cuproptosis mechanism. This study demonstrates that the constructed nanosystem can overcome tumor immune evasion, thereby providing a “trinity” model (epigenetic reprogramming, cuproptosis, and immune activation) for enhancing immunotherapy for melanoma, which also provides a valuable paradigm for the treatment of other tumors.