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Reshaping CAR-T cells through overexpression of T cell factor 1.

Hao Yao1,2, Yuntian Ding1,2,3, Qian Chen1,2

  • 1Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg University, Heidelberg, Germany.

Frontiers in Immunology
|November 26, 2025
PubMed
Summary

Restoring T cell factor 1 (TCF-1) in chimeric antigen receptor (CAR) T cells enhances their persistence and anti-tumor activity. This TCF-1 modulation improves CAR-T cell longevity and efficacy for hematologic malignancies.

Keywords:
CAR (chimeric antigen receptor) T cellsCRS - cytokine release syndromeT cell persistenceTCF (T-cell factor)immunotherapy

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Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Therapy

Background:

  • Chimeric antigen receptor (CAR) T cell therapy shows promise for hematologic malignancies.
  • Insufficient CAR-T cell persistence limits therapeutic efficacy.
  • T cell factor 1 (TCF-1) is vital for T cell memory and self-renewal but is underexpressed in CAR-T cells.

Purpose of the Study:

  • To investigate if restoring TCF-1 expression can improve CAR-T cell persistence and functionality.
  • To evaluate the impact of TCF-1 overexpression on CAR-T cell phenotype, proliferation, and anti-tumor activity.

Main Methods:

  • Human T cells were engineered with CAR vectors, with or without TCF-1.
  • Analyses included flow cytometry, cytokine profiling, killing assays, and RNA sequencing.
  • Machine learning was used for high-dimensional immunophenotyping.

Main Results:

  • TCF-1 overexpression reduced apoptosis and activation markers, increasing naive and stem cell-like subsets.
  • Modified CAR-T cells showed enhanced proliferative capacity, sustained cytotoxicity, and improved persistence.
  • Transcriptomic analysis revealed enrichment of cell cycle and metabolic pathways supporting longevity.

Conclusions:

  • TCF-1 overexpression enhances CAR-T cell persistence and anti-tumor efficacy by conferring resistance to apoptosis and promoting a less differentiated state.
  • TCF-1 modulation is a potential strategy to improve the durability and safety of CAR-T cell therapy for relapsed/refractory hematologic cancers.