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Charged substrate treatment enhances T cell mediated cancer immunotherapy

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  • Jia Song

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

  • Yanhui Lu

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

  • Lulu Liu

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

  • Xiaoyu Han

    (Peking University School and Hospital of Stomatology
    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
    Peking University School and Hospital of Stomatology)

  • Xin Zhang

    (Peking University Health Science Center)

  • Qun Cui

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

  • Ziqi Liu

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

  • Yusi Guo

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

  • Xiaona Zheng

    (Peking University School and Hospital of Stomatology
    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
    Peking University School and Hospital of Stomatology
    The First People’s Hospital of Jinzhong)

  • Xuliang Deng

    (Peking University School and Hospital of Stomatology
    Peking University School and Hospital of Stomatology)

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.

Suggested Citation

  • 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 & Xuliang Deng, 2025. "Charged substrate treatment enhances T cell mediated cancer immunotherapy," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56858-y
    DOI: 10.1038/s41467-025-56858-y
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    1. Xiaoshan Shi & Yunchen Bi & Wei Yang & Xingdong Guo & Yan Jiang & Chanjuan Wan & Lunyi Li & Yibing Bai & Jun Guo & Yujuan Wang & Xiangjun Chen & Bo Wu & Hongbin Sun & Wanli Liu & Junfeng Wang & Chenqi, 2013. "Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids," Nature, Nature, vol. 493(7430), pages 111-115, January.
    2. Fei Mo & Zhiya Yu & Peng Li & Jangsuk Oh & Rosanne Spolski & Liang Zhao & Caleb R. Glassman & Tori N. Yamamoto & Yun Chen & Filip M. Golebiowski & Dalton Hermans & Sonia Majri-Morrison & Lora K. Picto, 2021. "An engineered IL-2 partial agonist promotes CD8+ T cell stemness," Nature, Nature, vol. 597(7877), pages 544-548, September.
    3. Weiwei Yu & Zhen Wang & Xiafei Yu & Yonghui Zhao & Zili Xie & Kailian Zhang & Zhexu Chi & Sheng Chen & Ting Xu & Danlu Jiang & Xingchen Guo & Mobai Li & Jian Zhang & Hui Fang & Dehang Yang & Yuxian Gu, 2022. "Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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