2. Academic Validation
  3. Engineered probiotics recruit CAR macrophages and establish immune memory to eradicate heterogeneous glioblastoma in mice

Engineered probiotics recruit CAR macrophages and establish immune memory to eradicate heterogeneous glioblastoma in mice

  • Cell Host Microbe. 2026 Feb 11;34(2):212-229.e7. doi: 10.1016/j.chom.2025.12.014.
Yulin Zhang 1,  Jianyu Shen 2,  Yu Xu 3,  Fan Feng 2,  Xu Han 2,  Kaiyan Xi 2,  Zezheng Fang 2,  Yi Zhang 2,  Mingrui Wang 2,  Zixu Wang 2,  Pengfei Zhu 2,  Qikang Zhang 2,  Zhiqiang Li 2,  Baichuan Liu 2,  Zeyue Cao 2,  Chaoqun Wang 2,  Qianen Xu 2,  Yang Yu 2,  Chengpeng Sun 2,  Xinrui Wang 2,  Jingjing Wang 4,  Jiaojiao Pang 5,  Zimei Wu 4,  Huimin Geng 2,  Ahmet Acar 6,  Thomas Daubon 7,  Wenli Zhang 8,  Yanrong Zhang 9,  Xingang Li 2,  Yuguo Chen 10,  Shilei Ni 11,  Xinyi Jiang 12
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Qilu Hospital of Shandong University, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, Ministry of Education, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: [email protected].
  • 2 Department of Neurosurgery, Qilu Hospital of Shandong University, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, Ministry of Education, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Department of Neurosurgery, Qilu Hospital of Shandong University, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, Ministry of Education, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China; Department of Emergency Medicine, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.
  • 4 Faculty of Medicine and Health Sciences, School of Pharmacy, University of Auckland, Auckland 1023, New Zealand.
  • 5 Department of Emergency Medicine, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.
  • 6 Department of Biological Sciences, Middle East Technical University, Universiteler Mah. Dumlupınar Bulvarı 1, Çankaya, Ankara 06800, Turkey.
  • 7 University of Bordeaux, CNRS, IBGC UMR5095, Bordeaux, France.
  • 8 Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 9 College of Chemistry & Pharmacy, Northwest A&F University, Xianyang, Shaanxi 712100, China.
  • 10 Department of Emergency Medicine, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: [email protected].
  • 11 Department of Neurosurgery, Qilu Hospital of Shandong University, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, Ministry of Education, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: [email protected].
  • 12 Department of Neurosurgery, Qilu Hospital of Shandong University, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, Ministry of Education, Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: [email protected].
PMID: 41605215 DOI: 10.1016/j.chom.2025.12.014
Abstract

Glioblastoma (GBM) remains a highly lethal form of Cancer due to its molecular heterogeneity and the immunosuppressive microenvironment surrounding the tumor. Here, we report a modular immunotherapy platform characterized by its flexibility to simultaneously target multiple antigens. Specifically, we utilize engineered E. coli Nissle to colonize tumors and produce bispecific engagers that simultaneously target EGFRvIII and interleukin (IL)-13Rα2. These tags direct in situ-reprogrammed chimeric antigen receptor (CAR) macrophages, which are edited using nanoparticles and delivered within a shear-thinning hydrogel, to execute targeted phagocytosis. This probiotic-macrophage crosstalk eliminates tumor cells while converting protumor M2 macrophages into immunostimulatory M1 effectors. In aggressive orthotopic GBM mouse models, this strategy achieves 83% survival at the 120-day endpoint, representing a 5-fold improvement over single-target controls and establishing durable immunological memory that effectively combats recurrence. By functioning as multifunctional immune hubs, this platform offers a versatile framework designed to overcome the antigenic complexity of solid tumors.

Keywords

CAR macrophages; engineered probiotics; glioblastoma; immunotherapy; in situ gene editing; microbial immunotherapy; orthotopic models; tumor microenvironment.

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