Spatial Isolation of Single Copper(I) Sites for Cascade Enzyme‐Like Catalysis and Simultaneous Ferroptosis/Cuproptosis Boosted Immunotherapy

ABSTRACT Nanozyme‐based immunogenic cell death (ICD) inducers that effectively induce a strong immune response via enzyme‐like process have attracted great attention, but how to ensure controllable active sites and maximize site utilization remains a problem. Here, we report a structurally well‐defined and highly functional single‐site copper(I) nanomodulators termed CuNTD, constructed by precisely anchoring atomically dispersed self‐assembly S‐Cu(I)‐S sites onto a two‐dimensional Ti 3 C 2 surface. Leveraging Cu + with a higher catalytic efficiency than Cu 2+ , CuNTD generates reactive oxygen species (ROS) storms through photothermal‐enhanced cascade catalysis, further inducing mitochondrial dysfunction, ferroptosis and cuproptosis. Multifunctional CuNTD triggers strong ICD through cascade‐regulatory pathways of photothermal‐amplified ROS storms, cuproptosis and ferroptosis, effectively promoting dendritic cell maturation while reducing monotherapies side effects and resistance. In vivo, CuNTD combined with FDA‐approved immunoadjuvants significantly prolong the survival of mice. With its demonstrated biosafety and high efficiency as an ICD inducer, this study provides a promising framework for advancing augmented tumor immunotherapy with significant clinical potential.