肿瘤细胞治疗研究
英文原题：Engineered probiotics recruit CAR macrophages and establish immune memory to eradicate heterogeneous glioblastoma in mice.
在侵袭性原位GBM小鼠模型中，该策略在120天终点时实现了83%的生存率，相比单靶点对照组提高了5倍，并建立了有效对抗复发的持久免疫记忆。
胶质母细胞瘤（GBM）因其分子异质性及肿瘤周围免疫抑制微环境，仍是一种高度致命的癌症。在此，我们报道了一种模块化免疫治疗平台，其特点在于能够灵活地同时靶向多种抗原。具体而言，我们利用工程化大肠杆菌Nissle定植于肿瘤并产生双特异性衔接分子，同时靶向EGFRvIII和白细胞介素（IL）-13Rα2。这些标签引导原位重编程的嵌合抗原受体（CAR）巨噬细胞执行靶向吞噬作用，这些巨噬细胞通过纳米颗粒编辑并递送于剪切稀化水凝胶中。这种益生菌-巨噬细胞串扰在消除肿瘤细胞的同时，将促肿瘤M2巨噬细胞转化为免疫刺激性M1效应细胞。在侵袭性原位GBM小鼠模型中，该策略在120天终点时实现了83%的生存率，较单靶点对照组提高了5倍，并建立了有效对抗复发的持久免疫记忆。通过充当多功能免疫枢纽，该平台提供了一个旨在克服实体瘤抗原复杂性的通用框架。
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.
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