2. Academic Validation
  3. Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs

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

  • Nat Commun. 2026 Mar 31;17(1):3045. doi: 10.1038/s41467-026-70867-5.
Mingqi Hou # 1 2,  Wenjun Zhang # 3,  Ziping Qi # 1 4,  Guiming Li # 3,  Husheng Mei 3,  Shuang Qi 1 4 5,  Rui Jin 1 4,  Yuedong Zhao 3,  Xiaochen Tang 3,  Bing Xiu 3,  Xiaotong Chen 3,  Yunshuo Zhao 3,  Chen Hu 1 4 5,  Changlin Qian 6,  Xiuchun Li 3,  Zhan Xu 7,  Yongfei Chen 1 4,  Chao Wu 1 2,  Beilei Wang 1 4,  Lejin Yan 1 2,  Dan Li 7,  Yushan Huang 3,  Rui Liang 7,  Aoli Wang 1 4,  Jing Liu 1 2 4 5,  Wenchao Wang 1 2 4 5,  Bin Li 7,  Jun Long 3,  Ping Li 3,  Aibin Liang 8,  Qingsong Liu 9 10 11 12,  Jing Yang 13
Affiliations

Affiliations

  • 1 Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, PR China.
  • 2 University of Science and Technology of China, Hefei, Anhui, PR China.
  • 3 Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, PR China.
  • 4 Precision Cancer Medicine Engineering Research Center of Anhui Province, Hefei, Anhui, PR China.
  • 5 Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, PR China.
  • 6 Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
  • 7 Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
  • 8 Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, PR China. [email protected].
  • 9 Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, PR China. [email protected].
  • 10 University of Science and Technology of China, Hefei, Anhui, PR China. [email protected].
  • 11 Precision Cancer Medicine Engineering Research Center of Anhui Province, Hefei, Anhui, PR China. [email protected].
  • 12 Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, PR China. [email protected].
  • 13 Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, PR China. [email protected].
  • # Contributed equally.
PMID: 41916982 DOI: 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.

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