CAR-T cell therapy works well in blood cancers, but many patients still become resistant. A key reason is the presence of CAR-T regulatory T cells (CAR-Tregs), which weaken immune responses. Therefore, selectively targeting CAR-Tregs while preserving CAR-T activity remains a major challenge. Now, a pharmaceutical research team has identified a natural compound, timosaponin AIII (TAIII), that selectively eliminates CAR-T regulatory T cells. The study is published in Nature Communications.
The team was led by Prof. Liu Qingsong at the Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, in collaboration with Tongji University.
In this study, the researchers screened over 3,000 small molecules using a high-throughput platform. TAIII, a natural product derived from Anemarrhena asphodeloides, was identified as an effective regulator of T cell suppression. Further studies showed that TAIII blocks the adenosine A2A receptor, a key immune checkpoint, thereby reducing suppressive T cell activity.
In cell experiments, TAIII restored CAR-T function and enhanced its killing ability. In lymphoma models, combining TAIII with CAR-T therapy significantly inhibited tumor growth, reduced relapse, and extended survival. It also improved the effectiveness of patient-derived CAR-T cells.
In solid tumor models, TAIII reduced suppressive immune cells and increased cancer-killing T cells, making tumors more responsive to immunotherapy. It also showed strong synergy with CAR-T therapy and anti-PD-1 treatment.
Compared with an A2A receptor inhibitor currently in clinical trials, TAIII achieved similar antitumor effects at lower doses and with less frequent administration, suggesting good clinical potential.
“Our study suggests that TAIII is a promising natural immunomodulator that can improve CAR-T therapy by reducing immune suppression,” said Associate Professor Qi Ziping, a member of the team.
Publication details
Mingqi Hou et al, Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs, Nature Communications (2026). DOI: 10.1038/s41467-026-70867-5
Journal information:
Nature Communications
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Clinical categories
Provided by
Hefei Institutes of Physical Science, Chinese Academy of Sciences
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