哥伦比亚大学Michel Sadelain团队的一项最新研究发现了pTα增强mRNA翻译与CAR - T细胞根除实体肿瘤的能力。2025年12月2日出版的《细胞》发表了这项成果。

为了寻找增强CAR-T细胞功能持久性和效力的有效方法，该研究组探索了将前T细胞特征整合到典型的基于CD28的CAR中的潜力。胸腺细胞在β选择发育阶段发生增殖爆发，这是由前t细胞受体及其独特的pTα链驱动的。在多种液体和实体肿瘤模型中，携带pTα 1A结构域的CAR赋予T细胞更大的扩张、细胞因子的产生和体内持久性，同时降低衰竭和更大的长期肿瘤控制。结合1A结构域的CARs显示mRNA翻译主调控因子Y-Box结合蛋白1 （YBX1）的持续磷酸化，这是增强肿瘤根除所必需的。T细胞mRNA翻译的编程为调节和增强免疫治疗开辟了另一条途径。

据悉，目前的嵌合抗原受体（CAR）疗法对一系列血液系统恶性肿瘤和自身免疫性疾病有效，但对实体瘤的活性有限。

附：英文原文

Title: pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication

Author: Yuzhe Shi, Michael A. Lopez, Ivan S. Kotchetkov, Nayan Jain, Zeguo Zhao, Leena Halim, Anton Dobrin, Karlo Perica, Sophie A. Hanina, Vinagolu K. Rajasekhar, Michael G. Kharas, Michel Sadelain

Issue&Volume: 2025-12-02

Abstract: Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the β-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTα chain. CARs harboring the pTα 1A domain imparted greater expansion, cytokine production, and in vivo persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.

DOI: 10.1016/j.cell.2025.11.005

Source: https://www.cell.com/cell/abstract/S0092-8674(25)01254-1