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, it is necessary to selectively target CAR-Tregs while preserving CAR-T activity.

In a study published in Nature Communications, a research team led by Prof. LIU Qingsong from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences, along with collaborators from Tongji University, identified a natural compound, Timosaponin AIII (TAIII), that selectively eliminates CAR-Tregs.

The researchers screened over 3,000 small molecules using a high-throughput platform. They identified that TAIII, a natural product derived from Anemarrhena asphodeloides, was 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 inhibited tumor growth, reduced relapse, and extended survival. TAIII 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. TAIII also have strong synergy with CAR-T therapy and anti-PD-1 treatment. Compared with an A2A receptor inhibitor currently in clinical trials, TAIII achieved similar anti-tumor effects at lower doses and with less frequent administration, suggesting its good clinical potential.

"Our study suggests that TAIII is a promising natural immunomodulator that can improve CAR-T therapy by reducing immune suppression," said Assoc. Prof. QI Ziping, one author of this study.