肿瘤细胞治疗研究
英文原题：Synthetic M13 phage engagers expand CAR-T cell antigen recognition to overcome tumor heterogeneity.
肿瘤抗原异质性和 T 细胞抑制限制了CAR-T（CAR-T）细胞在实体瘤中的疗效。
肿瘤抗原异质性和T细胞抑制限制了CAR-T（CAR-T）细胞在实体瘤中的疗效。在此，我们构建了基于合成M13噬菌体的双特异性衔接器（BiPEs），使CAR-T细胞能够识别多种抗原并抵抗功能失调，从而介导广泛而持久的肿瘤清除。具体而言，BiPEs通过SpyTag-SpyCatcher将针对不同肿瘤靶点的单链抗体同时偶联至噬菌体pIII蛋白上。这些衔接器可将M13噬菌体特异性CAR-T（MCAR-T）细胞重定向，以清除异质性肿瘤亚克隆，并激发免疫以重塑CAR-T功能。在同基因胶质母细胞瘤模型中，BiPEs增强了MCAR-T对抗原多样性肿瘤细胞的疗效，与单靶点CAR-T相比显著延长了生存时间。关键的是，脂质纳米颗粒递送的MCAR mRNA在体内生成了具有有效多靶向活性的功能性CAR-T细胞。总之，这一模块化平台通过可编程的多靶点识别克服了抗原异质性和T细胞抑制，为实体瘤中的CAR治疗提供了一种可扩展的策略。
Tumor antigen heterogeneity and T cell inhibition limit the efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. Here, we engineered synthetic M13 bacteriophage-based bispecific engagers (BiPEs) that enable CAR-T cells to recognize multiple antigens and resist dysfunction, thus mediating broad and durable clearance of tumors. Specifically, BiPEs simultaneously conjugate single-chain antibodies against distinct tumor targets on phage pIII proteins via SpyTag-SpyCatcher. These engagers redirect M13 phage-specific CAR-T (MCAR-T) cells to eliminate heterogeneous tumor subclones and ignite immunity to remodel CAR-T function. In syngeneic glioblastoma models, BiPEs enhanced MCAR-T efficacy against antigenically diverse tumor cells, prolonging survival time significantly compared with single-target CAR-T. Critically, lipid nanoparticle-delivered MCAR mRNA generated functional CAR-T cells in vivo with effective multitargeting activity. In sum, this modular platform overcomes antigenic heterogeneity and T cell inhibition through programmable multitarget recognition, providing a scalable strategy for CAR therapy in solid tumors.
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