美国哈佛医学院Arlene H. Sharpe小组的研究开发出了STUB1-CHIC2复合物抑制CD8⁺ T细胞抑制肿瘤免疫。2025年8月12日出版的《自然—免疫学》发表了这项成果。

在这里，该课题组人员评估了899个CD8⁺ T细胞中响应小鼠黑色素瘤的基因，并确定E3泛素连接酶STUB1是抗肿瘤CD8⁺ T细胞功能的新的负调节因子。小组证明了敲除Stub1的CD8⁺ T细胞可以有效地控制多种小鼠模型的肿瘤生长。在机制上，STUB1与适配蛋白CHIC2相互作用，调节细胞因子受体在小鼠和人CD8⁺ T细胞中的表达。在这些受调控的细胞因子受体中，白细胞介素-27受体α (interleukin-27 receptor α)在Stub1/Chic2敲除CD8⁺ T细胞介导的肿瘤生长控制中起重要作用。总之，这些发现证实了STUB1-CHIC2复合物是CD8⁺ T细胞中细胞因子受体表达的调节因子，并为抑制该通路以增强CD8⁺ T细胞介导的抗肿瘤免疫提供了理论依据。

研究人员表示，CD8⁺ T细胞的体内CRISPR筛选先前已经发现了癌症免疫治疗的靶点；然而，基因组的一小部分已经被单独注释，这表明更多的调节因子仍有待发现。

附：英文原文

Title: A STUB1–CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity

Author: LaFleur, Martin W., Milling, Lauren E., Prathima, Priyamvada, Li, Vivian, Lemmen, Ashlyn M., Streeter, Ivy S. L., Heisig, Paul K. S., Derosia, Nicole M., Riffo, Elizabeth, Xu, Haonan, Nguyen, Thao H., Kolengaden, Aashiya, Markson, Samuel C., Doench, John G., Sharpe, Arlene H.

Issue&Volume: 2025-08-12

Abstract: In vivo CRISPR screens in CD8+ T cells have previously uncovered targets for cancer immunotherapy; however, a minority of the genome has been individually annotated, suggesting that additional regulators remain to be discovered. Here we assessed 899 genes in CD8+ T cells responding to murine melanoma and identified the E3 ubiquitin ligase STUB1 as a new negative regulator of anti-tumor CD8+ T cell function. We demonstrated that Stub1 knockout CD8+ T cells effectively control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. Among the regulated cytokine receptors, interleukin-27 receptor α is essential for tumor growth control mediated by Stub1/Chic2 knockout CD8+ T cells. Together, these findings establish the STUB1–CHIC2 complex as a regulator of cytokine receptor expression in CD8+ T cells and provide rationale for inhibiting this pathway to enhance CD8+ T cell-mediated anti-tumor immunity.

DOI: 10.1038/s41590-025-02231-6

Source: https://www.nature.com/articles/s41590-025-02231-6