Bimetallic Nanoreactor Activates cGAS‐STING Pathway via mtDNA Release for Cancer Metalloimmunotherapy

Abstract Manganese‐based materials are promising candidates for supporting cyclic dinucleotides for activating the cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway, which is crucial for inducing immune responses against cancer. However, their limited capacity to independently stimulate the STING pathway restricts their clinical potential. To overcome this limitation, a bimetallic nanoreactor (MCC) is developed to activate the cGAS‐STING pathway for metalloimmunotherapy. Upon cellular uptake, MCC induces mitochondrial and cellular damage by generating toxic hydroxyl radicals and causing calcium ions overload, subsequently leading to the release of mitochondrial DNA (mtDNA) and tumor‐associated antigens. The released mtDNA, in combination with manganese ions, effectively activates the cGAS‐STING pathway, improving the antigen‐presenting capacity of antigen‐presenting cells (APCs) and stimulating adaptive immune responses. In vivo experiments demonstrate that MCC substantially inhibits tumor growth in B16‐OVA and 4T1 tumor models, while promoting the infiltration of T lymphocytes and APCs into the tumor, accompanied by increased immune cell levels in the tumor‐draining lymph node and spleen. Moreover, MCC effectively reduces lung metastasis of melanoma in combination with anti‐programmed death 1. These results emphasize MCC as a non‐nucleotide, bimetallic manganese‐calcium STING nanoagonist for cancer metalloimmunotherapy, providing a promising paradigm for treating primary as well as metastatic tumors.