近日，南京大学宋玉君团队揭示了代谢劫持工程益生菌重编程肿瘤代谢和免疫微环境，用于自我强化光动力免疫治疗。该研究于2025年10月8日发表在《美国化学会志》上。

代谢劫持破坏肿瘤氧化还原稳态和重编程免疫代谢串扰。然而，现有的方法缺乏代谢扰动和免疫原性激活之间的综合协调，以实现自我增强的光动力-免疫治疗协同作用。

研究组设计了一种上转换纳米颗粒(UCNP)-细菌杂交系统，它在消耗甘氨酸的同时在肿瘤中产生光敏剂原卟啉IX （PpIX）。研究组重新编程大肠杆菌1917益生菌，使其表达谷氨酰tRNA还原酶A和苹果酸合成酶B合成5-氨基乙酰丙酸，肿瘤细胞将其转化为PpIX。微流控芯片筛选优化了利用甘氨酸作为其唯一碳源的细菌，而UCNP-DNA通过G4-发夹和细菌适体与细菌结合，响应肿瘤miRNA-21形成捕获PpIX和扩增PDT的G-四联体。

这种双重代谢系统通过甘氨酸耗竭破坏肿瘤对ROS的自我保护，并通过功能化的UCNPs丰富光敏剂，从而实现自我增强的PDT。此外，它还促进ROS介导的免疫原性细胞死亡、树突状细胞活化和M1巨噬细胞极化，表现出明显的抗肿瘤生长和转移。

附：英文原文

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

Author: Shurong Qin, Qi Wang, Zhuangwei Zhang, Junhui Gu, Guanzhong He, Fei Zeng, Ruiyue Chen, Bangshun He, Yuzhen Wang, Meng Wang, Yujun Song

Issue&Volume: October 8, 2025

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.

DOI: 10.1021/jacs.5c10242

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c10242