Nanomedicine leverages cuproptosis-mediated cGAS-STING activation to enhance antitumor immunity.

The cGAS-STING pathway is a cornerstone of innate immunity, sensing cytosolic DNA to initiate potent type I interferon and inflammatory responses. Its targeted activation represents a promising strategy to overcome cancer immunosuppression and resistance. However, the clinical translation of conventional STING agonists is hindered by poor pharmacokinetics, lack of tumor specificity, and systemic toxicity. Recent advances highlight a crucial interaction between the cGAS-STING pathway and cuproptosis, a novel copper-dependent form of regulated cell death driven by mitochondrial metabolism. Nanomedicine offers a transformative platform for exploiting this synergy. Specifically, engineered nanoplatforms can induce cuproptosis within tumor cells, leading to mitochondrial damage and the release of mitochondrial DNA (mtDNA) into the cytosol. This released mtDNA serves as a potent endogenous ligand to activate the cGAS-STING pathway. The subsequent cascade results in robust production of type I interferons and pro-inflammatory cytokines, which remodel the tumor microenvironment by promoting dendritic cell maturation, macrophage repolarization, and cytotoxic T-cell infiltration. This bridges a unique immunogenic cell death mechanism with the activation of systemic antitumor immunity. This review outlines the cGAS-STING signaling axis and its role in cancer, details the functional interplay with cuproptosis, and focuses on recent nanomedicine strategies designed to leverage this cuproptosis-mtDNA -cGAS-STING axis to potentiate antitumor immunity. We further discuss current challenges and future perspectives for this innovative combinatorial immunotherapy approach. Overall, this article highlights promising nanomedicine-based avenues that leverage the cGAS-STING-cuproptosis interplay for cancer therapy.