Song Jia, Lu Yanhui, Liu Lulu, Han Xiaoyu, Meng Yanhong, Heng Boon Chin, Zhang Xin, Cui Qun, Liu Ziqi, Guo Yusi, Zheng Xiaona, You Fuping, Lu Dan, Zhang Xuehui, Deng Xuliang
Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, PR China.
Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, PR China.
Nat Commun. 2025 Feb 12;16(1):1585. doi: 10.1038/s41467-025-56858-y.
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.
生物物理线索在T细胞生物学中起着至关重要的作用，但其在过继性T细胞疗法（ACT）中的影响在很大程度上仍不清楚。在此，我们使用由具有可调表面电荷强度的电活性纳米复合材料组成的带电基质，研究电刺激对CD8 T细胞的影响。电刺激增强了转移T细胞的持久性和肿瘤抑制功效，其效果取决于基质电荷。单细胞RNA测序分析揭示了虚拟记忆T（Tvm）细胞减少，增殖潜能T（Tpp）细胞增加，相对于用不带电基质处理的细胞，Tpp细胞表现出更强的抗肿瘤活性和代谢适应性。ATAC-seq分析表明，对Tpp细胞分化至关重要的转录因子EGR1的上游结合位点的可及性增加。从机制上讲，带电基质破坏离子型TCR-脂质相互作用，放大TCR信号，并激活EGR1，从而在体外培养过程中阻碍Tvm极化。因此，我们的研究结果突出了细胞外电刺激在塑造T细胞命运中的重要性，为优化ACT用于治疗应用提供了潜力。
