2. Academic Validation
  3. Piezo1-mediated mechano-energetics regulate CAR T cell function

Piezo1-mediated mechano-energetics regulate CAR T cell function

  • Res Sq. 2025 Oct 23:rs.3.rs-7776704. doi: 10.21203/rs.3.rs-7776704/v1.
Ngoc Luu 1,  Rui Li 2,  Yifei Fang 1,  Huishu Wang 1,  Yujing Song 2,  Ruiqi Chen 1,  Xiangyi Fang 3 4,  Junru Liao 5,  Tracy Chen 2,  Andre Kelly 3 4,  Alexander A Shestov 3,  Katsuo Kurabayashi 2,  Roddy O'Connor 3 4,  Louis Hodgson 6 7,  Saba Ghassemi 3 4,  Weiqiang Chen 1 2 8
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, Tandon School of Engineering, New York University, Brooklyn, NY 11201, USA.
  • 2 Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, Brooklyn, NY 11201, USA.
  • 3 Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, Brooklyn, NY 11201, USA.
  • 6 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 7 Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 8 Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.
PMID: 41282104 DOI: 10.21203/rs.3.rs-7776704/v1
Abstract

CAR T cell cytotoxicity requires generating immense mechanical force, but the energetic costs of this process remain poorly defined. While metabolic reprogramming fuels effector function, its mechanistic connection to mechanotransduction remains unclear. By directly measuring the synaptic force and mechanical energy of single CAR T cells and linking them to their metabolic state, we proved that the mechano-energetic efficiency is a fundamental determinant of cytotoxic potency. We discovered that the mechanosensitive ion channel Piezo1 couples cytoskeletal dynamics to metabolic rewiring via CA2+-Wnt-Rac1 signaling. Disrupting Piezo1 cripples glycolytic and mitochondrial ATP production, causing energetic stress and impaired cytotoxicity. Notably, Piezo1 activity follows a Goldilocks principle: intermediate level maximizes activation and cytotoxicity, whereas either hypoactive or hyperactive Piezo1 states impair mechano-metabolic fitness and drive dysfunction in patient and exhausted CAR T cells. Our work establishes mechano-metabolic coupling as a core regulator of CAR T cell fitness and pinpoints Piezo1 tuning as a new strategy to enhance Cancer Immunotherapy.

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