Cu-Mn nanocomposite for enhanced tumor cuproptosis achieved by remodeling the tumor microenvironment and activating the antitumor immunogenic responses.

Cuproptosis is a newly discovered mode of cell death, which is caused by excess copper and results in cell death via the mitochondrial pathway. However, the complex tumor microenvironment (TME) is characterized by many factors, including high levels of glutathione and lack O2, limit the application of traditional cuproptosis agents in antitumor therapy. Herein, we report a hyaluronic acid modified copper-manganese composite nanomedicine (CMCNs@HA) to remodel the TME and facilitate efficient cuproptosis in tumor. The integration of CuO2 and MnO2 into CMCNs@HA endows this nanoplatform to generate O2 and deplete GSH in tumor site, ensuring the environment is beneficial to the cuproptosis of tumor. The glutathione (GSH) depletion process is accompanied by the release of Mn2+ ions. The released Mn2+ ions improve the cuproptosis through efficient chemodynamic therapy and initiate immune response via activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which significantly suppresses tumor growth and inhibits tumor metastases. In addition, the Mn2+ ions release process enables this nanoplatform to work as activable T1 contrast agent to achieve accurate tumor diagnosis. This functionally complementary composite metal nanomaterial may provide effective ideas regarding the application of cuproptosis in designing tumor therapeutic regimens. STATEMENT OF SIGNIFICANCE: Cuproptosis in combination with cGAS-STING offers significant potential for tumor treatment. Here, we constructed TME responsive copper-manganese composite nanomaterials (CMCNs@HA) to augment tumor cuproptosis. GSH depletion, hypoxia relief, and effective chemodynamic therapy caused by CMCNs@HA facilitate the progression of cuproptosis. Besides, CMCNs@HA successfully initiate immune response via activating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and significantly inhibits tumor metastases. Simultaneously, released Mn2+ ions provide real-time magnetic resonance imaging (MRI) signal changes, enabling accurate tumor diagnosis and monitoring of the therapeutic process.