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

Date

2026-02-11

Author

Zhang, Yulin
Shen, Jianyu
Xu, Yu
Feng, Fan
Han, Xu
Xi, Kaiyan
Fang, Zezheng
Zhang, Yi
Wang, Mingrui
Wang, Zixu
Zhu, Pengfei
Zhang, Qikang
Li, Zhiqiang
Liu, Baichuan
Cao, Zeyue
Wang, Chaoqun
Xu, Qianen
Yu, Yang
Sun, Chengpeng
Wang, Xinrui
Wang, Jingjing
Pang, Jiaojiao
Wu, Zimei
Geng, Huimin
Acar, Ahmet
Daubon, Thomas
Zhang, Wenli
Zhang, Yanrong
Li, Xingang
Chen, Yuguo
Ni, Shilei
Jiang, Xinyi

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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.

Subject Keywords

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

URI

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105029284294&origin=inward
https://hdl.handle.net/11511/118557

Collections

Department of Biology, Article