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  3. Amplifying antigen-induced cellular responses with proximity labelling

Amplifying antigen-induced cellular responses with proximity labelling

  • Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09518-6.
Shuojun Li # 1,  Yinghui Men # 1 2,  Zihan Wang # 1,  Yingcheng Wu # 3,  Hao Sun 1,  Mingyang Yin 4,  Xinrui Fan 1,  Guiyun Deng 5,  Zhicheng Yang 6,  Tiange Yang 4,  Yudian Xiao 1,  Hu Zhou 6,  Guangchuan Wang 4,  Jia Fan 3,  Chenqi Xu 4,  Qiang Gao 7,  Shuo Han 8
Affiliations

Affiliations

  • 1 Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Key Laboratory of RNA Innovation Science and Engineering, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 2 Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Zhongshan Hospital; Institutes of Biomedical Sciences; State Key Laboratory of Genetics and Development of Complex Phenotypes; Human Phenome Institute, Fudan University, Shanghai Academy of Natural Sciences, Shanghai, China.
  • 4 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 5 College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 7 Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Zhongshan Hospital; Institutes of Biomedical Sciences; State Key Laboratory of Genetics and Development of Complex Phenotypes; Human Phenome Institute, Fudan University, Shanghai Academy of Natural Sciences, Shanghai, China. gaoqiang@fudan.edu.cn.
  • 8 Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Key Laboratory of RNA Innovation Science and Engineering, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. shuohan@sibcb.ac.cn.
  • # Contributed equally.
PMID: 40931066 DOI: 10.1038/s41586-025-09518-6
Abstract

Antigen-induced clustering of cell surface receptors, including T cell receptors and Fc Receptors, represents a widespread mechanism in cell signalling activation1,2. However, most naturally occurring antigens, such as tumour-associated antigens, stimulate limited receptor clustering and on-target responses owing to insufficient density3-5. Here we repurpose proximity labelling6, a method used to biotinylate and identify spatially proximal proteins, to amplify designed probes as synthetic antigen clusters on the cell surface. We develop an in vivo proximity-labelling technology controlled by either red light or ultrasound to covalently tag fluorescein probes at high density near a target antigen. Using T cell receptors as an example, we demonstrate that the amplified fluorescein effectively clusters and directs a fluorescein-binding bispecific T cell engager to induce enhanced T cell activation and cytotoxicity. Noninvasive, tissue-selective labelling in multiple syngeneic mouse tumour models produces potent immune responses that rapidly eradicate treated tumours. Efficient Cell Lysis further promotes epitope spreading to induce systemic immunity against untreated distal lesions and immune memory against rechallenge. Thus, proximity-labelling chemistry holds promise as a generalized strategy to manipulate antigen-dependent receptor function and cell states.

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