Metabolic Hijacking by Engineered Probiotics Reprograms Tumor Metabolism and Immune Microenvironment for Self-Reinforcing Photodynamic Immunotherapy
Shurong Qin, Qi Wang, Zhuangwei Zhang, Jason Gu, Guanzhong He, Fei Zeng, Ruiyue Chen, Bangshun He, Yuzhen Wang, Meng Wang, Yujun Song
Abstract
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 E. coli 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.