2026-04-15 合肥物質科学研究院（HFIPS）
Timosaponin AIII (TAIII) enhances the anti-tumor efficacy of CAR-T cells in vitro and in vivo. (Image by HOU Mingqi)
＜関連情報＞
- https://english.hf.cas.cn/nr/bth/202604/t20260415_1156333.html
- https://www.nature.com/articles/s41467-026-70867-5
チモサポニンAIIIはCAR-T細胞の効力を高め、CAR-Treg細胞の機能を阻害することで再発を予防する Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs
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 Yang
Nature Communications Published:31 March 2026
DOI:https://doi.org/10.1038/s41467-026-70867-5
Abstract
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.
