Palbociclib and rapamycin pretreatment boosted the persistence and functionality of CAR-T cells in solid tumors through metabolic reprogramming
4 affiliations
- 1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023 China
- 2Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, No. 23 Pingjiang Road Hexi District, Tianjin, 300211 China
- 3Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- 4Peking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010000 China
Abstract
Background: Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable success in treating hematologic malignancies; however, its efficacy against solid tumors remains limited due to the immunosuppressive tumor microenvironment. Enhancing CAR-T cell persistence and function through the use of culture media additives offers a potential strategy to overcome these challenges.
Methods: We conducted a systematic evaluation of CAR-T cell culture media additives and selected five FDA-approved compounds—decitabine, palbociclib, metformin, enasidenib, and rapamycin—based on their diverse mechanisms of action and clinical safety profiles. Anti-mesothelin (MSLN) CAR-T cells were generated and assessed under hypoxic in vitro conditions and in two subcutaneous solid tumor mouse models. The effects of individual and combinatorial additive treatments on CAR-T cell function were evaluated. To elucidate the underlying mechanisms, we performed RNA sequencing and metabolic analyses.
Results: All five additives partially reversed hypoxia-induced dysfunction in CAR-T cells, with palbociclib, enasidenib, and rapamycin demonstrating the most significant enhancement of cytotoxicity in both 2D and 3D assays. Notably, the combination of palbociclib and rapamycin (Pal + Rap) yielded pronounced additive improvements in CAR-T function, markedly enhancing CAR-T cell persistence, tumor-killing activity, and resistance to tumor recurrence in both HCC1806 and Capan-2 xenograft models. Transcriptomic and metabolic profiling showed concurrent upregulation of oxidative phosphorylation and improved in vivo anti-tumor function in Pal + Rap-preconditioned hypoxic CAR-T cells.
Conclusions: Preconditioning CAR-T cells with palbociclib and rapamycin enhances their metabolic fitness and anti-tumor efficacy under hypoxia, offering a simple and clinically feasible strategy to improve CAR-T therapy against solid tumors.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08749-z.
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BibTeX
@article{zhou2026palbociclib,
title = {{Palbociclib and rapamycin pretreatment boosted the persistence and functionality of CAR-T cells in solid tumors through metabolic reprogramming}},
author = {Muya Zhou and Lianfeng Zhao and Zhiying Chen and Wenwen Chen and Luxia Xu and Jiaqi Liu and Jinhua Hu and Jialu Hong and Feiyan Pan and Zhigang Hu and Lingfeng He and Zhiqiang Wang and Tangfeng Lv and Xudong Ao and Zhigang Guo},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08749-z},
url = {https://doi.org/10.1186/s12967-026-08749-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Palbociclib and rapamycin pretreatment boosted the persistence and functionality of CAR-T cells in solid tumors through metabolic reprogramming
AU - Muya Zhou
AU - Lianfeng Zhao
AU - Zhiying Chen
AU - Wenwen Chen
AU - Luxia Xu
AU - Jiaqi Liu
AU - Jinhua Hu
AU - Jialu Hong
AU - Feiyan Pan
AU - Zhigang Hu
AU - Lingfeng He
AU - Zhiqiang Wang
AU - Tangfeng Lv
AU - Xudong Ao
AU - Zhigang Guo
PY - 2026
DA - 2026/08/07
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08749-z
UR - https://doi.org/10.1186/s12967-026-08749-z
AB - Background: Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable success in treating hematologic malignancies; however, its efficacy against solid tumors remains limited due to the immunosuppressive tumor microenvironment. Enhancing CAR-T cell persistence and function through the use of culture media additives offers a potential strategy to overcome these challenges. Methods: We conducted a systematic evaluation of CAR-T cell culture media additives and selected five FDA-approved compounds—decitabine, palbociclib, metformin, enasidenib, and rapamycin—based on their diverse mechanisms of action and clinical safety profiles. Anti-mesothelin (MSLN) CAR-T cells were generated and assessed under hypoxic in vitro conditions and in two subcutaneous solid tumor mouse models. The effects of individual and combinatorial additive treatments on CAR-T cell function were evaluated. To elucidate the underlying mechanisms, we performed RNA sequencing and metabolic analyses. Results: All five additives partially reversed hypoxia-induced dysfunction in CAR-T cells, with palbociclib, enasidenib, and rapamycin demonstrating the most significant enhancement of cytotoxicity in both 2D and 3D assays. Notably, the combination of palbociclib and rapamycin (Pal + Rap) yielded pronounced additive improvements in CAR-T function, markedly enhancing CAR-T cell persistence, tumor-killing activity, and resistance to tumor recurrence in both HCC1806 and Capan-2 xenograft models. Transcriptomic and metabolic profiling showed concurrent upregulation of oxidative phosphorylation and improved in vivo anti-tumor function in Pal + Rap-preconditioned hypoxic CAR-T cells. Conclusions: Preconditioning CAR-T cells with palbociclib and rapamycin enhances their metabolic fitness and anti-tumor efficacy under hypoxia, offering a simple and clinically feasible strategy to improve CAR-T therapy against solid tumors. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08749-z.
SN - 1479-5876
ER -