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<p>Chimeric antigen receptor (CAR)-T cell therapy has transformed treatment of relapsed/refractory DLBCL, yet resistance driven by regulatory T cells (Tregs) limits its efficacy. Here we identify Timosaponin AIII (TAIII), a clinical-stage natural product, as an effective modulator of CAR-T function that depletes CAR-Tregs while enhancing effector activity. Mechanistically, TAIII acts as an allosteric A2AR inhibitor by competing with cholesterol, suppressing CREB-dependent FoxP3 transcription and disrupting the A2AR-Treg axis. Ablation of A2AR or Tregs in vitro and in vivo abolishes TAIII activity, confirming specificity. Furthermore, TAIII reduces intratumoral Tregs, increases CD8⁺ T cells infiltration, and potentiates PD-1 blockade in solid tumor models. Importantly, TAIII promotes central memory T-cell formation and enhances CAR-T cytotoxic cytokine secretion. Combining or pretreating CAR-T cells with TAIII markedly improves antitumor efficacy and prevents late relapse across preclinical models. These findings establish TAIII as a combinatorial strategy to deplete CAR-Tregs, enhance CAR-T activity, and extend therapeutic durability.</p>

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Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Mingqi Hou,
  • Wenjun Zhang,
  • Ziping Qi,
  • Guiming Li,
  • Husheng Mei,
  • Shuang Qi,
  • Rui Jin,
  • Yuedong Zhao,
  • Xiaochen Tang,
  • Bing Xiu,
  • Xiaotong Chen,
  • Yunshuo Zhao,
  • Chen Hu,
  • Changlin Qian,
  • Xiuchun Li,
  • Zhan Xu,
  • Yongfei Chen,
  • Chao Wu,
  • Beilei Wang,
  • Lejin Yan,
  • Dan Li,
  • Yushan Huang,
  • Rui Liang,
  • Aoli Wang,
  • Jing Liu,
  • Wenchao Wang,
  • Bin Li,
  • Jun Long,
  • Ping Li,
  • Aibin Liang,
  • Qingsong Liu,
  • Jing Yang

摘要

Chimeric antigen receptor (CAR)-T cell therapy has transformed treatment of relapsed/refractory DLBCL, yet resistance driven by regulatory T cells (Tregs) limits its efficacy. Here we identify Timosaponin AIII (TAIII), a clinical-stage natural product, as an effective modulator of CAR-T function that depletes CAR-Tregs while enhancing effector activity. Mechanistically, TAIII acts as an allosteric A2AR inhibitor by competing with cholesterol, suppressing CREB-dependent FoxP3 transcription and disrupting the A2AR-Treg axis. Ablation of A2AR or Tregs in vitro and in vivo abolishes TAIII activity, confirming specificity. Furthermore, TAIII reduces intratumoral Tregs, increases CD8⁺ T cells infiltration, and potentiates PD-1 blockade in solid tumor models. Importantly, TAIII promotes central memory T-cell formation and enhances CAR-T cytotoxic cytokine secretion. Combining or pretreating CAR-T cells with TAIII markedly improves antitumor efficacy and prevents late relapse across preclinical models. These findings establish TAIII as a combinatorial strategy to deplete CAR-Tregs, enhance CAR-T activity, and extend therapeutic durability.