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.
摘要：
刺激环磷酸鸟苷(GMP)-磷酸腺苷(AMP)合酶(cGAS)-干扰素基因刺激物(STING)途径是细菌激活肿瘤免疫系统的关键策略。然而,有限的刺激能力对推进细菌免疫疗法提出了重大挑战.这里,一种腺苷5'-三磷酸(ATP)响应性锰(Mn)基细菌材料(E.大肠杆菌@PDMC-PEG（聚乙二醇）工程成功，表现出协同激活cGAS-STING途径的特殊能力。在肿瘤微环境中，其特征是ATP水平升高，这种生物混合材料降解，导致二价锰离子（Mn2+）的释放和随后的细菌暴露。这种组合协同激活cGAS-STING途径，因为Mn2+增强了cGAS对细菌分泌的细胞外DNA(eDNA)的敏感性。体内实验的结果表明,生物杂合材料大肠杆菌@PDMC-PEG和VNP20009@PDMC-PEG有效抑制小鼠皮下黑素瘤和兔原位肝癌的生长。本文提供了基于细菌的肿瘤免疫治疗的发展的有价值的见解。
