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  3. Synthetic M13 phage engagers expand CAR-T cell antigen recognition to overcome tumor heterogeneity

Synthetic M13 phage engagers expand CAR-T cell antigen recognition to overcome tumor heterogeneity

  • Trends Biotechnol. 2026 Mar 28:S0167-7799(26)00047-8. doi: 10.1016/j.tibtech.2026.02.008.
Fan Feng 1,  Xu Han 1,  Zezheng Fang 1,  Kaiyan Xi 1,  Zixu Wang 1,  Jianyu Shen 1,  Yi Zhang 1,  Mingrui Wang 1,  Zhiqiang Li 1,  Xuan Han 2,  Kaijie Zhao 1,  Huimin Geng 1,  Yanrong Zhang 3,  Wenli Zhang 4,  Zimei Wu 5,  Songbai Gui 6,  Yulin Zhang 7,  Shilei Ni 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Qilu Hospital, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China.
  • 2 Beijing Key Laboratory of Carcinogenesis and Translational Research, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 3 College of Chemistry & Pharmacy, Northwest A&F University, Xianyang, Shaanxi 712100, China.
  • 4 Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 5 Faculty of Medicine and Health Sciences, School of Pharmacy, University of Auckland, Auckland 1023, New Zealand.
  • 6 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, Qilu Hospital, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China. Electronic address: [email protected].
  • 8 Department of Neurosurgery, Qilu Hospital, Shandong Key Laboratory of Brain Health and Function Remodeling, Institute of Brain and Brain-Inspired Science, Jinan Microecological Biomedicine Shandong Laboratory, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China. Electronic address: [email protected].
PMID: 41904099 DOI: 10.1016/j.tibtech.2026.02.008
Abstract

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.

Keywords

CAR-T; bacteriophage; phage display; tumor heterogeneity.

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