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The fundamental reason for the failure of glioblastoma (GBM) treatment is not merely the strong invasiveness of the tumor, but rather the highly heterogeneous antigens + myeloid immune suppression-dominated microenvironment, which makes single-targeted CAR-T or CAR-M therapy difficult to be sustained and effective. The authors did not continue with "stacking targets" or "increasing doses", but instead constructed a self-sustaining local immune system.
This work reported by Jiang Xinyi, Ni Shilei, Chen Yuguo, and Zhang Yulin proposes a highly modular treatment platform: engineered probiotics + in situ edited CAR macrophages + injectable hydrogel biomaterials. Among them, engineered E. coli Nissle can selectively colonize in the GBM microenvironment and continuously secrete bispecific engagement molecules through a population sensing lysis circuit, while marking two types of tumor antigens, EGFRvIII and IL-13Rα2, fundamentally avoiding immune escape caused by antigen loss.
At the material level, the authors did not use the traditional in vitro CAR cell preparation method, but utilized the virus-biologically inspired nanodelivery system (VMTNs) to reprogram macrophages in the tumor local area into universal CAR-M; at the same time, by cutting and diluting alginate hydrogels, they constructed a "surgical cavity immune niche" to achieve spatial co-localization and long-term retention of cells, bacteria, and nanomaterials.
More importantly, this system does not stop at tumor clearance, but through the cross-talk between macrophages and microorganisms, reprograms TAMs into APCs with antigen-presenting functions, thereby activating CD8⁺ T cells and establishing systemic, CD8⁺-dependent immune memory. In highly invasive in situ GBM mouse models, this strategy achieved a long-term survival rate of over 80% and successfully blocked tumor recurrence in the contralateral brain region. The relevant study, titled "Engineered probiotics recruit CAR macrophages and establish immune memory to eradicate heterogeneous glioblastoma in mice", was published in Cell Host & Microbe.
Original link: https://www.sciencedirect.com/science/article/abs/pii/S1931312825005335?via%3Dihub=
