A Single‐Atom Mn/MoO3−x Nanoagonist for Cascade cGAS/STING Activation in Tumor‐Specific Catalytic Metalloimmunotherapy

Abstract 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, Mn 2+ and MoO 4 2− can be responsively released from Mn/MoO 3− x SANA and enhance the sensitivity of cGAS to dsDNA. Importantly, MoO 4 2− with a relatively slow‐release profile and facile cellular accumulation compensates for Mn 2+ 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.