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Cell Reports Medicine

Cell Reports Medicine

IF: 11.7
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Miltefosine reinvigorates exhausted T?cells by targeting their bioenergetic state

Published:17 December 2024 DOI: 10.1016/j.xcrm.2024.101869 PMID: 39657666
Xingying Zhang,?Chenze Zhang,?Shan Lu,?Jingxi Dong,?Na Tang,?Yao Wang,?Weidong Han,?Xi Pan,?Xiang Zhang,?Duan Liu,?Ng Shyh-Chang,?Yu Wang,?Guihai Feng,?Haoyi Wang

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.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Miltefosine 58066-85-6 C21H46NO4P 314 suppliers $8.00-$4974.00
Miltefosine 58066-85-6 C21H46NO4P 314 suppliers $8.00-$4974.00
Miltefosine 58066-85-6 C21H46NO4P 314 suppliers $8.00-$4974.00
Miltefosine 58066-85-6 C21H46NO4P 314 suppliers $8.00-$4974.00

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