State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P.R. China.
Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Nat Commun. 2023 Feb 16;14(1):865. doi: 10.1038/s41467-023-36523-y.
Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8 T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC.
虽然放射疗法可以促进抗肿瘤免疫，但这种现象的机制尚不清楚。在这里，我们证明了肿瘤中 E3 泛素连接酶、肿瘤细胞内在的三联基序蛋白 21（TRIM21）的表达与鼻咽癌（NPC）对放射治疗的反应和 CD8 T 细胞介导的抗肿瘤免疫呈负相关。TRIM21 的敲除调节了 cGAS/STING 细胞质 DNA 感应途径，增强了 NPC 细胞的抗原呈递能力，并激活了细胞毒性 T 细胞介导的抗肿瘤免疫反应，以响应放射治疗。在机制上，TRIM21 通过 K48 连接的泛素化促进了线粒体电压依赖性阴离子选择通道蛋白 2（VDAC2）的降解，这抑制了 VDAC2 寡聚体形成的孔，从而抑制了放射暴露后的 I 型干扰素反应。在 NPC 患者中，高表达 TRIM21 与预后不良和放射治疗后早期肿瘤复发有关。我们的研究结果揭示了 TRIM21 在放射诱导的抗肿瘤免疫中的关键作用，为提高 NPC 患者放射治疗的疗效提供了潜在的靶点。
