Charged substrate treatment enhances T cell mediated cancer immunotherapy

Jia Song, Yanhui Lu, Lulu Liu, Xiaoyu Han, Yanhong Meng, Boon Chin Heng, Xin Zhang, Qun Cui, Ziqi Liu, Yusi Guo, Xiaona Zheng, Fuping You, Dan Lu (), Xuehui Zhang () and Xuliang Deng ()
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Jia Song: Peking University School and Hospital of Stomatology
Yanhui Lu: Peking University School and Hospital of Stomatology
Lulu Liu: Peking University School and Hospital of Stomatology
Xiaoyu Han: Peking University School and Hospital of Stomatology
Yanhong Meng: Peking University School and Hospital of Stomatology
Boon Chin Heng: Peking University School and Hospital of Stomatology
Xin Zhang: Peking University Health Science Center
Qun Cui: Peking University School and Hospital of Stomatology
Ziqi Liu: Peking University School and Hospital of Stomatology
Yusi Guo: Peking University School and Hospital of Stomatology
Xiaona Zheng: Peking University School and Hospital of Stomatology
Fuping You: Peking University Health Science Center
Dan Lu: Peking University Health Science Center
Xuehui Zhang: Peking University School and Hospital of Stomatology
Xuliang Deng: Peking University School and Hospital of Stomatology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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+ 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.

Date: 2025
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DOI: 10.1038/s41467-025-56858-y

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