Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state

T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner. Impressively, in the terminally exhausted state where PD-1 antibody treatment is ineffective, miltefosine still enhances CAR-T cell activity. Single-cell sequencing analysis reveals that miltefosine treatment significantly increases the population of effector cells. Mechanistically, miltefosine improves impaired glycolysis and oxidative phosphorylation in hypofunctional CAR-T cells. In both allogeneic and syngeneic tumor models, miltefosine effectively enhances the solid tumor clearance ability of CAR-T cells and T cells, demonstrating its potential as an effective immunotherapeutic drug.

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Publication Details

Journal
Cell Reports Medicine
Published
2024-12-01
DOI
https://doi.org/10.1016/j.xcrm.2024.101869
Citations
4
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
1.13

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article

Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state

Shan Lu, Chenze Zhang, Ng Shyh‐Chang, Guihai Feng et al.
4 citations
Cell Reports Medicine
CAR-T cell therapy research
1.13
article

Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state

Shan Lu, Chenze Zhang, Ng Shyh‐Chang, Guihai Feng, Haoyi Wang, Weidong Han, Jingxi Dong, Yao Wang, Xiang Zhang, Yu Wang, Xi Pan, Na Tang, Xingying Zhang, Duan Liu
article en
4 citations

Abstract

T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner. Impressively, in the terminally exhausted state where PD-1 antibody treatment is ineffective, miltefosine still enhances CAR-T cell activity. Single-cell sequencing analysis reveals that miltefosine treatment significantly increases the population of effector cells. Mechanistically, miltefosine improves impaired glycolysis and oxidative phosphorylation in hypofunctional CAR-T cells. In both allogeneic and syngeneic tumor models, miltefosine effectively enhances the solid tumor clearance ability of CAR-T cells and T cells, demonstrating its potential as an effective immunotherapeutic drug.

Cell Reports MedicineVol. 5(12)
Beijing University of Chinese Medicine (CN), Shenzhen University (CN), Chinese Academy of Sciences (CN), Institute of Zoology (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, China Postdoctoral Science Foundation, Institute of Zoology, Chinese Academy of Sciences, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities
Openalex Percentile: Top 18%
CAR-T cell therapy research
1.13
DOIOpen Access PDFOpenAlex
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