Self-Carrier Nanoagonist Enabling Positive Feedback Regulation of Cuproptosis-Immunity for Potent Antitumor Therapy

Cuproptosis-based immunotherapy shows significant potential in the treatment of cancer. However, its therapeutic effectiveness is hampered by inefficient copper delivery, poor targeting, tumor metabolic reprogramming, and the immunosuppressive tumor microenvironment. Herein, a self-carrier nanoagonist was constructed to achieve positive feedback regulation of cuproptosis-immunity for potent antitumor therapy. The nanoagonist, as a cuproptosis inducer assembled from nucleotides and copper ions, resulted in mitochondrial damage and mitochondrial DNA (mtDNA) release, thereby promoting immunogenic cell death (ICD) and stimulator of interferon gene (STING) activation. Notably, the metal-coordination-driven nanoagonist also functioned as a mimic of the natural STING agonist 2',3'-cyclic GMP-AMP (2',3'-cGAMP), directly stimulating the STING pathway. Density functional theory calculations were performed to elucidate the geometry of the nanoagonist, while dynamic molecular docking analyses demonstrated a high binding affinity between the nanoagonist and STING. In turn, STING activation, combined with 2-deoxy-d-glucose, modulated tumor cell metabolic pathways by blocking glycolysis to alleviate tumor cell tolerance to copper and sensitize cuproptosis, further inducing ICD and amplifying the STING signal. In vivo experiments demonstrated that the reciprocal amplification between cuproptosis and the STING pathway remodeled the immune microenvironment and enhanced the efficacy of antitumor immunotherapy. The work offers a promising strategy to potentiate the cancer-immunity cycle and improve immunotherapy outcomes.