西安交通大学第一附属医院李磊研究小组取得一项新突破。他们揭示了泛素化导向的胞质DNA降解控制cGAS-STING介导的DNA损伤免疫反应。2026年1月8日，国际知名学术期刊《癌细胞》发表了这一成果。

该课题组发现泛素化导向的细胞质DNA降解是DNA损伤后cGAS-STING激活的关键决定因素。从机制上讲，胞质DNA外切酶TREX1被E3泛素连接酶SPOP降解，但被去泛素酶USP7反向稳定。癌症相关的SPOP突变或USP7过表达可提高TREX1水平，促进胞质DNA降解并损害cGAS-STING介导的免疫激活。值得注意的是，在接受放化疗的患者中，USP7表达升高与肿瘤浸润淋巴细胞减少和疾病进展加速相关。

此外，USP7抑制剂降低TREX1水平并恢复放射后的免疫反应。这些发现阐明了DNA损伤与免疫激活之间的联系机制，并强调了USP7抑制剂作为放射免疫治疗的潜在增强剂。

据悉，癌细胞中cGAS-STING信号的激活需要由内在或治疗诱导的DNA损伤产生的细胞质DNA。然而，利用这一途径改善免疫治疗的临床努力取得了有限的成功，突出了在理解DNA损伤和免疫治疗之间的联系方面的差距。

附：英文原文

Title: Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage

Author: Lei Li, Qi Ye, Jinlu Ma, Zixi Wang, Tianjie Liu, Yuzeshi Lei, Mingming Lu, Jialu Kang, Haohan Xiang, Buyun Li, Shan Xu, Ke Wang, Yule Chen, Jiaqi Chen, Bohan Ma, Wenyue Huang, Mengjiao Cai, Nan Wu, Yanqiang Li, Jiale An, Chongming Jiang, Rui Ye, Jing Liu, Steven H. Lin, Yang Gao, Jian Ma, Lei Li

Issue&Volume: 2026-01-08

Abstract: Activation of cGAS-STING signaling in cancer cells requires cytosolic DNA produced by intrinsic or treatment-induced DNA damage. However, clinical efforts to exploit this pathway to improve immunotherapy have yielded limited success, highlighting gaps in understanding the link between DNA damage and immunotherapy. Here, we identify ubiquitination-directed cytosolic DNA degradation as a critical determinant for cGAS-STING activation following DNA damage. Mechanistically, the cytosolic DNA exonuclease TREX1 is degraded by the E3 ubiquitin ligase SPOP but is reversely stabilized by the deubiquitinase USP7. Cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and impairing cGAS-STING-mediated immune activation. Notably, elevated USP7 expression correlates with reduced tumor-infiltrating lymphocytes and accelerated disease progression in patients undergoing chemoradiotherapy. Furthermore, USP7 inhibitors reduce TREX1 levels and restore immune responses following radiation. These findings elucidate the mechanisms linking DNA damage to immune activation and highlight USP7 inhibitors as potential enhancers of radioimmunotherapy.

DOI: 10.1016/j.ccell.2025.12.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00547-1