A Single‐Atom Mn/MoO ₃₋ <i> _x </i> Nanoagonist for Cascade cGAS/STING Activation in Tumor‐Specific Catalytic Metalloimmunotherapy

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway plays a crucial role in initiating anti-tumor immunity. Despite the development of various STING agonists, their effectiveness is often limited by suboptimal activation efficiency and poor sustainability. To address this, a Mn/MoO_3- _x nanoagonist featuring Mn single-atom sites is presented, designed for cascade cGAS/STING activation in tumor-specific catalytic metalloimmunotherapy. The single-atom nanoagonist (SANA) is meticulously crafted by doping Mn atoms into defective molybdenum oxide (MoO_3- _x), enabling robust peroxidase-mimicking catalysis and inducing severe double-stranded DNA (dsDNA) damage in tumors. Of note, Mn²⁺ and MoO₄ ^2- can be responsively released from Mn/MoO_3- _x SANA and enhance the sensitivity of cGAS to dsDNA. Importantly, MoO₄ ^2- with a relatively slow-release profile and facile cellular accumulation compensates for Mn²⁺ that has poor cellular accumulation due to continuous efflux, thus continuatively triggering the secretion of type I interferon for beyond 72 h. Remarkably, Mn/MoO_3- _x SANA significantly inhibits tumor growth and metastasis without supplementary STING agonists or external stimulation. This study offers a promising cascade cGAS/STING activation approach to enhance the efficacy and sustainability of catalytic metalloimmunotherapy.