Piezo1-mediated mechano-energetics regulate CAR T cell function.

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• CAR T cell therapy efficacy relies on mechanical force generation.
• The link between cellular metabolism and mechanotransduction in CAR T cells is not well understood.
• Metabolic reprogramming is crucial for CAR T cell effector functions.

Purpose of the Study:

• To investigate the relationship between mechanical energy expenditure and metabolic state in single CAR T cells.
• To identify the molecular mechanisms connecting mechanotransduction and metabolic reprogramming in CAR T cells.
• To explore Piezo1 as a potential therapeutic target for enhancing CAR T cell function.

Main Methods:

• Direct measurement of synaptic force and mechanical energy in single CAR T cells.
• Analysis of metabolic states in conjunction with mechanical measurements.
• Investigation of Ca2+-Wnt-Rac1 signaling pathways involving Piezo1.
• Assessment of CAR T cell function in patient-derived and exhausted cells.

Main Results:

• Mechano-energetic efficiency directly correlates with CAR T cell cytotoxic potency.
• The mechanosensitive ion channel Piezo1 integrates cytoskeletal dynamics with metabolic rewiring.
• Piezo1 disruption impairs ATP production and leads to energetic stress and reduced cytotoxicity.
• An intermediate level of Piezo1 activity optimizes CAR T cell function, while extremes lead to dysfunction.

Conclusions:

• Mechano-metabolic coupling is a critical regulator of CAR T cell fitness.
• Piezo1 plays a key role in linking mechanical force to cellular metabolism and function.
• Tuning Piezo1 activity presents a novel strategy to improve CAR T cell-based cancer immunotherapy.