Preprint / Version 1

Catch-bond engineering surpasses high-affinity maturation in T cell receptor therapies for solid tumors

This article is a preprint and has not been certified by peer review.

Authors

    Tianqi Huang,  
    Tianqi Huang
    Runyu Wang,  
    Runyu Wang
    • Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University
    • School of Chemistry and Molecular Engineering, East China Normal University
    Dinglin Zhang,  
    Dinglin Zhang
    Siqi Wu,  
    Siqi Wu
    Yuanhao Wang,  
    Yuanhao Wang
    Jianglai Wang,  
    Jianglai Wang
    Zhengxu Ren,  
    Zhengxu Ren
    Sifan Wang,  
    Sifan Wang
    Lan Li,  
    Lan Li
    Yan Zhou,  
    Yan Zhou
    Xiaojing Wang,  
    Xiaojing Wang
    Yanling Bao,  
    Yanling Bao
    Mingyu Fan,  
    Mingyu Fan
    Luxue Zhang,  
    Luxue Zhang
    Junshuang Liu,  
    Junshuang Liu
    Wenjie Yuan,  
    Wenjie Yuan
    Huairui Yuan,  
    Huairui Yuan
    Sirui Li,  
    Sirui Li
    Bo Sun,  
    Bo Sun
    Fei Shao,  
    Fei Shao
    • Shanghai General Hospital
    Chenqi Xu,  
    Chenqi Xu
    • Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
    Guohui Li,  
    Guohui Li
    Anhui Wang,  
    Anhui Wang
    Wenmao Huang,  
    Wenmao Huang
    • Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University
    Xiang Zhao
    Xiang Zhao
Categories
Immunology & Microbiology

Abstract

The sensitivity of T cell receptors (TCRs) has traditionally been attributed to their affinity, a principle that haslong underpinned both T cell biology and TCR engineering. Currently, high-affinity maturation remains the predominant strategy employed to enhance TCR sensitivity; however, this approach has been associated with severe off-target toxicities in clinical settings. In this study, using the only FDA-approved TCR-T therapy as a clinical reference, we demonstrate that force-induced catch bonds, rather than static affinity, primarilydetermine TCR sensitivity and facilitate the development of more effective TCR engineering strategies. Among polar and charged amino acids, histidine was determined to be the most effective residue for pinpointing engineering hotspots. TCRs engineered to form catch bonds exhibited superior performance compared to the FDA-approved TCR subjected to high-affinity maturation, improving the efficacy of TCR-T cell therapiesagainst solid tumors without eliciting off-target toxicity or alloreactivity. Mechanistically, a correlation was observed between TCR sensitivity and the strength of catch bonds, whereas no such relationship was found with affinity. The duration of T cell–tumor cell interactions, immunological synapse formation, and the intensity of subsequent signaling are governed by catch bonds rather than by affinity. Structural and computational investigations have demonstrated that force-induced reconfiguration of the ligand-receptor interface, along with the formation of a novel hydrogen bond network, augments the specificity of interactions between the TCR and antigenic peptides. Furthermore, bispecific T cell engagers utilizing the TCR scaffold also formed catch bonds with tumor antigens, indicating intrinsic mechanosensory properties of the extracellular domains of TCRs and suggesting a novel therapeutic modality based on catch-bond-engineered TCRs.

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2026-07-28

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Huang, T., Wang, R., Zhang, D., Wu, S., Wang, Y., Wang, J., Ren, Z., Wang, S., Li, L., Zhou, Y., Wang, X., Bao, Y., Fan, M., Zhang, L., Liu, J., Yuan, W., Yuan, H., Li, S., Sun, B., … Zhao, X. (2026). Catch-bond engineering surpasses high-affinity maturation in T cell receptor therapies for solid tumors. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.07.28.000297

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