Programmable bacteria-driven biohybrid triggers spatiotemporal-controlled STING activation to potentiate...

Cuproptosis, a novel copper-mediated programmed cell death, has emerged as a highly promising therapeutic avenue. However, its efficacy is limited by tumor glycolytic metabolism and the immunosuppressive microenvironment. Here, we propose an innovative biohybrid system (denoted as DB@CSCN) to synergistically induce cuproptosis and STING pathway stimulation for high-efficiency tumor-targeted precise immunotherapy. This system leverages engineered Escherichia coli (E. coli) bacteria (DacA-Bac), genetically programmed to produce the STING activator cyclic di-adenosine monophosphate (CDA), and functionalized with Cu-SF(CuS) nanoparticles through synthetic biology approaches-a design which enables the precise and safe tumor-targeted release of STING agonists, overcoming key limitations of passive nanocarrier delivery. Exploiting the hypoxic tropism feature of the strain, DB@CSCN selectively accumulates in the tumor region and responsively dissociates, releasing copper ions to induce copper-overload-mediated cuproptosis. Moreover, the release of CDA from DacA-Bac can be spatiotemporally controlled under laser irradiation, ensuring precise delivery of STING agonists to the tumor site. Notably, we discover that CDA-induced STING activation amplifies cuproptosis, which is potentially caused by the disrupting of glycolysis in tumor cells, boosting the overall synergistic therapeutic efficacy. This combination treatment further enhances dendritic cells (DCs) maturation, T cell immunity, and antitumor immune responses, effectively restraining tumor proliferation and metastasis. This study provides valuable insights into the interplay between the STING immune pathway and cuproptosis via modulation of glycolysis, paving the way for the development of next-generation antitumor immunotherapies.