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Exploring Mechano-metabolomic Pathways in CAR T cells

ABSTRACT: Mechanical force generation at the immunological synapse is a hallmark of CAR T cell cytotoxicity and a key indicator of functional potency, yet the underlying mechanisms are not fully understood. Here, we performed real-time single-cell analysis to quantify the spatiotemporal dynamics of synaptic force and metabolic activity in CAR T cells upon CD19 antigen engagement. We identified a Piezo1–Ca²⁺–Wnt signaling axis that integrates mechanical sensing with cytoskeletal remodeling and metabolic reprogramming. This mechano-metabolic coupling drives CAR T cell activation and varies across different CAR constructs, patient-derived products, and manufacturing conditions. Notably, functional heterogeneity among CAR T cells correlates with differences in their mechanical force profiles and energetic output. Our findings reveal a reciprocal relationship between mechanotransduction and metabolic switching, providing new insight into CAR T cell biology. This framework may inform the development of screening tools and engineering strategies to enhance CAR T cell mechanical fitness, energetic resilience, and therapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306574 | GEO | 2025/10/02

REPOSITORIES: GEO

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Differential Gene Expression During CAR T Cells Activation

Project description:Mechanical force generation at the immunological synapse is a hallmark of CAR T cell cytotoxicity and a key determinant of functional potency. However, the underlying mechanobiological mechanisms remain poorly understood. Here, we real-time measured the mechanical allostasis of single CAR T cells involving spatiotemporal dynamics of synaptic force and cellular metabolic activity upon CD19 antigen activation, and revealed that the CAR T cell activation is governed by sophisticated mechano-energetic mechanisms. We identify a Piezo1–Ca²⁺–Wnt axis that integrates force transduction with actin remodeling and metabolic reprogramming. Notably, functional heterogeneity across CAR T cell products from different patients as well as with different designs and manufacturing protocols correlates with variation in this mechano-metabolic program. Our findings revealed the reciprocal relationship between mechanosensation and metabolic switch, thus providing a new framework for (pre-)clinical screening of CAR T cell functional state and engineering CAR T cells with enhanced mechanical fitness, energetic resilience, and therapeutic efficacy.

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Project description:Exploring Mechano-metabolomic Pathways in CAR T cells

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