Metabolic Hijacking by Engineered Probiotics Reprograms Tumor Metabolism and Immune Microenvironment for Self-Reinforcing Photodynamic Immunotherapy

Metabolic hijacking disrupts tumor redox homeostasis and reprograms immune-metabolic crosstalk. Nevertheless, existing approaches lack integrated coordination between metabolic perturbation and immunogenic activation to achieve self-reinforcing photodynamic-immunotherapy synergy. Here, we designed an upconversion nanoparticle (UCNP)-bacteria hybrid system that depletes glycine while generating the photosensitizer protoporphyrin IX (PpIX) in tumors. We reprogrammed <i><i>E. coli</i></i> 1917 probiotics to express glutamyl-tRNA reductase A and malate synthase B to synthesize 5-aminolevulinic acid, which tumor cells convert into PpIX. Microfluidic-chip screening optimized bacteria to utilize glycine as their sole carbon source, while UCNP-DNA through G4-hairpin and bacterial aptamers binds to bacteria, responding to tumor miRNA-21 to form G-quadruplexes that trap PpIX and amplify PDT. This dual metabolic system disrupts tumor self-protection against ROS by glycine depletion and enriches photosensitizers by functionalized-UCNPs, enabling self-reinforcing PDT. Additionally, it promotes ROS-mediated immunogenic cell death, dendritic cell activation, and M1 macrophage polarization, exhibiting robust antitumor growth and metastasis.