ATP‐Responsive Manganese‐Based Bacterial Materials Synergistically Activate the cGAS‐STING Pathway for Tumor Immunotherapy

Abstract Stimulating the cyclic guanosine monophophate(GMP)‐adenosine monophosphate (AMP) synthase (cGAS)‐stimulator of interferon genes (STING) pathway is a crucial strategy by which bacteria activate the tumor immune system. However, the limited stimulation capability poses significant challenges in advancing bacterial immunotherapy. Here, an adenosine 5′‐triphosphate (ATP)‐responsive manganese (Mn)‐based bacterial material (E. coli@PDMC‐PEG (polyethylene glycol)) is engineered successfully, which exhibits an exceptional ability to synergistically activate the cGAS‐STING pathway. In the tumor microenvironment, which is characterized by elevated ATP levels, this biohybrid material degrades, resulting in the release of divalent manganese ions (Mn²⁺) and subsequent bacteria exposure. This combination synergistically activates the cGAS‐STING pathway, as Mn²⁺ enhances the sensitivity of cGAS to the extracellular DNA (eDNA) secreted by the bacteria. The results of the in vivo experiments demonstrate that the biohybrid materials E. coli@PDMC‐PEG and VNP20009@PDMC‐PEG effectively inhibit the growth of subcutaneous melanoma in mice and in situ liver cancer in rabbits. Valuable insights for the development of bacteria‐based tumor immunotherapy are provided here.