Charged substrate treatment enhances T cell mediated cancer immunotherapy
Biophysical cues play a crucial role in T cell biology, yet their implications in adoptive T cell therapy (ACT) remain largely unknown. Here, we investigate the effect of electrical stimuli on CD8<sup>+</sup> T cells using a charged substrate composed of electroactive nanocomposites with tunable surface charge intensities. Electrical stimuli enhance the persistence and tumor-suppressive efficacy of transferred T cells, with effects dependent on substrate charge. Single-cell RNA-sequencing analysis unveils a decrease in virtual memory T (Tvm) cells and an increase in proliferative potential T (Tpp) cells, which exhibit superior antitumor activity and metabolic adaptations relative to those treated with uncharged substrate. ATAC-seq profiling demonstrates heightened accessibility at upstream binding sites for EGR1, a transcription factor critical for Tpp cell differentiation. Mechanistically, the charged substrate disrupts ionic TCR-lipid interactions, amplifies TCR signaling, and activates EGR1, thereby impeding Tvm polarization during ex vivo culture. Our findings thus highlight the importance of extracellular electrical stimuli in shaping T cell fate, offering potential for optimizing ACT for therapeutic applications.
Authors
- Boon Chin Heng (ORCID: https://orcid.org/0000-0003-2541-3699)
- Yanhui Lu (ORCID: https://orcid.org/0009-0009-1354-0122)
- Fuping You (ORCID: https://orcid.org/0000-0002-7444-729X)
- Dan Lü (ORCID: https://orcid.org/0000-0002-3000-5094)
- Yusi Guo (ORCID: https://orcid.org/0009-0001-4383-6436)
- Xuliang Deng (ORCID: https://orcid.org/0000-0003-1838-6274)
- Jia Song (ORCID: https://orcid.org/0000-0003-1418-3656)
- Xuehui Zhang (ORCID: https://orcid.org/0000-0003-1016-6488)
- Ziqi Liu (ORCID: https://orcid.org/0000-0003-4109-4245)
- Yanhong Meng (ORCID: https://orcid.org/0000-0002-2054-8503)
- Xiaona Zheng (ORCID: https://orcid.org/0000-0002-7554-5916)
- Qun Cui (ORCID: https://orcid.org/0000-0001-9081-7687)
- Xiaoyu Han (ORCID: https://orcid.org/0009-0006-5482-4162)
- Lulu Liu (ORCID: https://orcid.org/0000-0002-5577-7058)
- Xin Zhang (ORCID: https://orcid.org/0009-0003-1112-6397)
Institutions
- King University (US)
- Peking University (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Second People 's Hospital of Jinzhong (CN)
- Peking University School and Hospital of Stomatology (CN)
- National Clinical Research (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1038/s41467-025-56858-y
- Citations
- 6
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 6.27
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Beijing Municipality
- National Key Research and Development Program of China