Orchestrated copper-loaded nanoreactor for simultaneous induction of cuproptosis and immunotherapeutic intervention in colorectal cancer

Ion interference, including intracellular copper (Cu) overload, disrupts cellular homeostasis, triggers mitochondrial dysfunction, and activates cell-specific death channels, highlighting its significant potential in cancer therapy. Nevertheless, the insufficient intracellular Cu ions transported by existing Cu ionophores, which are small molecules with short blood half-lives, inevitably hamper the effectiveness of cuproptosis. Herein, the ESCu@HM nanoreactor, self-assembled from the integration of H-MnO 2 nanoparticles with the Cu ionophore elesclomol (ES) and Cu, was fabricated to facilitate cuproptosis and further induce relevant immune responses. Specifically, the systemic circulation and tumoral accumulation of Cu, causing irreversible cuproptosis, work in conjunction with Mn 2+ , resulting in the repolarization of tumor-associated macrophages (TAMs) and amplification of the activation of the cGAS-STING pathway by damaged DNA fragments in the nucleus and mitochondria. This further stimulates antitumor immunity and ultimately reprograms the tumor microenvironment (TME) to inhibit tumor growth. Overall, ESCu@HM as a nanoreactor for cuproptosis and immunotherapy, not only improves the dual antitumor mechanism of ES and provides potential optimization for its clinical application, but also paves the way for innovative strategies for cuproptosis-mediated colorectal cancer (CRC) treatment. Scheme 1 . A schematic illustration of ESCu@HM-induced cuproptosis and activation of the cGAS-STING pathway for colorectal cancer immunotherapy. The liberated ES, which may concurrently efflux, chelate and transport additional extracellular Cu into cancer cells, along with Cu would trigger the aggregation of dihydrolipoamide acetyltransferase (DLAT) and the destabilization of Fe-S cluster proteins, resulting in cuproptosis. Concurrently, the released Mn 2+ could further enhance the sensitivity of the dsDNA sensor cGAS and amplify the activation of the STING pathway.