肿瘤细胞治疗研究
英文原题：Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs.
嵌合抗原受体（CAR）-T 细胞疗法已改变了复发/难治性 DLBCL 的治疗，但由调节性 T 细胞（Tregs）驱动的耐药限制了其疗效。
嵌合抗原受体（CAR）T 细胞疗法已改变复发/难治性弥漫大 B 细胞淋巴瘤（DLBCL）的治疗，但调节性 T 细胞（Treg）驱动的耐药限制其疗效。本研究发现，处于临床开发阶段的天然产物 Timosaponin AIII（TAIII）可有效调节 CAR-T 功能，减少 CAR-Treg 并增强效应活性。从机制上看，TAIII 通过与胆固醇竞争发挥变构 A2AR 抑制剂作用，抑制 CREB 依赖的 FoxP3 转录并破坏 A2AR-Treg 轴。在体外和体内敲除 A2AR 或去除 Treg 后，TAIII 的作用均消失，证实了其作用特异性。此外，TAIII 可减少肿瘤内 Treg、增加 CD8 T 细胞浸润，并增强实体瘤模型对 PD-1 阻断的应答。值得注意的是，TAIII 促进中央记忆 T 细胞形成并增强 CAR-T 细胞毒性细胞因子分泌。在临床前模型中，将 TAIII 与 CAR-T 细胞联合使用或预处理 CAR-T 细胞，均显著增强抗肿瘤疗效并防止晚期复发。这些发现确立了 TAIII 作为联合策略的潜力，可减少 CAR-Treg、增强 CAR-T 活性并延长疗效持续时间。
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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