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Mechanical force regulates the inhibitory function of PD-1.

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Title: Mechanical force regulates the inhibitory function of PD-1.
Authors: Chen H; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. cdchenhui@ibp.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. cdchenhui@ibp.ac.cn., Zhang Y; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, China., Cui L; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, China., Fan J; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the MOE Frontier Science Center for Brain Science & Brain-machine Integration, State Key Laboratory for Modern Optical Instrumentation Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China.; School of Basic Medical Sciences, Henan University, Zhengzhou, Henan, China., Zhu H; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the MOE Frontier Science Center for Brain Science & Brain-machine Integration, State Key Laboratory for Modern Optical Instrumentation Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China.; China Resources Sanjiu Medical & Pharmaceutical Co., Ltd., Shenzhen, 518000, China., Wu S; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China., Zhou H; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, China., Zhang Y; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, China., Song G; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, China., Jiang N; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA., Zhu M; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, China., Lou C; Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang, China. 601245@hrbmu.edu.cn., Chen W; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the MOE Frontier Science Center for Brain Science & Brain-machine Integration, State Key Laboratory for Modern Optical Instrumentation Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China. jackweichen@zju.edu.cn.; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. jackweichen@zju.edu.cn., Lou J; State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. jlou@ibp.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. jlou@ibp.ac.cn.
Source: EMBO reports [EMBO Rep] 2026 Apr; Vol. 27 (7), pp. 1789-1812. Date of Electronic Publication: 2026 Feb 25.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 100963049 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-3178 (Electronic) Linking ISSN: 1469221X NLM ISO Abbreviation: EMBO Rep Subsets: MEDLINE
Imprint Name(s): Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Oxford, UK : Published for EMBO by Oxford University Press, 2000-
MeSH Terms: Programmed Cell Death 1 Receptor*/metabolism , Programmed Cell Death 1 Receptor*/chemistry , Programmed Cell Death 1 Receptor*/genetics , B7-H1 Antigen*/metabolism , B7-H1 Antigen*/chemistry , B7-H1 Antigen*/genetics, T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Programmed Cell Death 1 Ligand 2 Protein/metabolism ; Programmed Cell Death 1 Ligand 2 Protein/chemistry ; Humans ; Molecular Dynamics Simulation ; Protein Binding ; Animals
Abstract: The immune checkpoint molecule, programmed cell death 1 (PD-1), critically regulates T-cell activation upon binding PD-L1 or PD-L2, making it a key target in cancer immunotherapy. Although extensively studied, the molecular mechanism of the inhibitory function of PD-1 remains incompletely understood. Using the biomembrane force probe (BFP), we measure catch-slip bond behavior between PD-1 and PD-L1/PD-L2 under force. Steered molecular dynamics (SMD) simulation reveals a force-induced bound state distinct from the force-free state observed in solved complex structures. Disrupting interactions that stabilize either state weakens the catch bond, and diminishes the inhibitory function of PD-1. Interestingly, soluble forms of PD-L1/PD-L2 compete with their surface-bound counterparts and attenuate PD-1-mediated T-cell inhibition, suggesting that soluble PD-1 ligands could potentially serve as anti-PD-1 drugs. Tumor growth studies using a gain of function mutant based on the catch-bond mechanism confirm the anti-cancer activity of soluble PD-L1. Our findings highlight that mechanical force governs the inhibitory function of PD-1 and suggest that PD-1 acts as a mechanical sensor in T-cell suppression. Thus, mechanical regulation should be considered when designing PD-1 blocking therapies.
(© 2026. The Author(s).)
Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests.
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Grant Information: T2394512 MOST | National Natural Science Foundation of China (NSFC); 32200549 MOST | National Natural Science Foundation of China (NSFC); 32090044 MOST | National Natural Science Foundation of China (NSFC); 11672317 MOST | National Natural Science Foundation of China (NSFC); T2394511 MOST | National Natural Science Foundation of China (NSFC); 12172371 MOST | National Natural Science Foundation of China (NSFC); 32301035 MOST | National Natural Science Foundation of China (NSFC); XDB37020102 Strategic Priority Research Program of the Chinese Academy of Sciences; YZTZ-2022-0080-0015 Beijing Medical Award Foundation ( ); 242102310348 | Henan Provincial Science and Technology Research Project ( )
Contributed Indexing: Keywords: Immunological Synapse; Immunotherapy; Mechanical Force; PD-1; T Cells
Substance Nomenclature: 0 (Programmed Cell Death 1 Receptor)
0 (B7-H1 Antigen)
0 (Programmed Cell Death 1 Ligand 2 Protein)
0 (PDCD1 protein, human)
0 (CD274 protein, human)
Entry Date(s): Date Created: 20260225 Date Completed: 20260709 Latest Revision: 20260821
Update Code: 20260821
PubMed Central ID: PMC13076993
DOI: 10.1038/s44319-026-00715-6
PMID: 41741724
Database: MEDLINE
Description
ISSN:1469-3178
DOI:10.1038/s44319-026-00715-6