Defective Single-Site Nanozymes with Exposed Unsaturated Cu–N ₂ Sites for Antitumor Immunotherapy via Innate Immune-Checkpoint Blockade

Disrupting the redox balance of tumor cells while blocking MER proto-oncogene tyrosine kinase (MerTK)-mediated macrophage efferocytosis can simultaneously awaken and enhance innate and adaptive antitumor immunity. Herein, we develop an MRX-2843 (MerTK inhibitor) and Mn²⁺ codelivered defective metal-organic framework (copper-2,3,6,7,10,11-hexaiminotriphenylene (Cu-HITP))-based single-site nanozyme (Ir@D-Cu-HITP-MMP) for antitumor immunotherapy via innate immune-checkpoint blockade. Highly exposed unsaturated Cu-N₂ sites feature asymmetric electron distribution, inducing localized electron polarization and exhibiting excellent enzyme-like catalytic performance for reactive oxygen species (ROS) generation. The ROS surge disrupts redox homeostasis, impairing mitochondrial function and adenosine triphosphate production, while affecting copper transport for cuproptosis and suppressing heat shock protein expression to facilitate mild photothermal therapy. Furthermore, the tumor microenvironment-triggered release of MRX-2843 inhibits macrophage efferocytosis, increasing tumor immunogenicity and promoting prolonged cyclic GMP-AMP (cGAMP) transport. This synergizes with Mn²⁺ to enhance the stimulator of interferon genes (STING) activation, triggering robust immune responses. Overall, Ir@D-Cu-HITP-MMP demonstrates potent antitumor effects by activating powerful innate and adaptive immune responses.