FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy

Nature. 2024 May;629(8010):201-210. doi: 10.1038/s41586-024-07242-1. Epub 2024 Apr 10.


Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Forkhead Box Protein O1* / genetics
  • Forkhead Box Protein O1* / metabolism
  • Humans
  • Immunotherapy, Adoptive*
  • Mice
  • Mitochondria / metabolism
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Phenotype
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / metabolism
  • Stem Cells* / cytology
  • Stem Cells* / immunology
  • Stem Cells* / metabolism
  • T-Lymphocytes* / cytology
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism
  • Tumor Microenvironment / immunology


  • Forkhead Box Protein O1
  • FOXO1 protein, human
  • Receptors, Chimeric Antigen