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Metabolic reprogramming via FOXP3 engineering: A Novel strategy to enhance CAR-T cell efficacy in solid tumors

Cellular & Molecular Immunology volume 22, pages 809–810 (2025)Cite this article

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FOXP3-engineered CAR-T cells represent a novel therapeutic approach that redefines metabolic adaptability in solid tumors. In a recent article on cell metabolism, Niu et al. demonstrated that cytoplasmic FOXP3 reprograms CAR-T cell metabolism by engaging Drp1 and promoting mitochondrial fusion and fatty acid oxidation, which results in enhanced persistence and tumor clearance without triggering immunosuppressive activity. This research highlights the key findings of this work and explores the implications of using spatial FOXP3 dynamics to modulate CAR-T cell function.

Chimeric antigen receptor (CAR) T cells have demonstrated remarkable efficacy in the treatment of hematological malignancies but present significant challenges when applied to solid tumors. A key limitation is insufficient metabolic adaptability and functional exhaustion in the tumor microenvironment (TME) [1, 2]. Conventional T cells depend heavily on glycolysis and oxidative phosphorylation (OXPHOS), which are often impaired in nutrient-deprived, hypoxic TMEs [3, 4]. In contrast, regulatory T (Treg) cells utilize fatty acid oxidation (FAO) to sustain their survival and function under these adverse conditions [5, 6]. This metabolic distinction not only facilitates Treg cell survival in the TME but also suppresses the functionality of effector T (Teff) cells and CD8+ T cells. Consequently, enhancing the metabolic adaptability of CAR-T cells represents a promising strategy to overcome TME-mediated limitations [7].

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  1. Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine and Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Dan Li, Siyuan Qiang & Bin Li

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  1. Dan Li
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Correspondence to Dan Li or Bin Li.

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The authors declare that they have no competing interests. Dr. Bin Li is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Li, D., Qiang, S. & Li, B. Metabolic reprogramming via FOXP3 engineering: A Novel strategy to enhance CAR-T cell efficacy in solid tumors. Cell Mol Immunol 22, 809–810 (2025). https://doi.org/10.1038/s41423-025-01315-5

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