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
  • 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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