Gou Qian, Yan Bingjun, Duan Yalan, Guo Yilei, Qian Jing, Shi Juanjuan, Hou Yongzhong
School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, People's Republic of China.
Adv Sci (Weinh). 2025 Feb;12(5):e2412205. doi: 10.1002/advs.202412205. Epub 2024 Dec 12.
In addition to adaptive immune checkpoint of PD-1/PD-L1, the innate immune checkpoint SIRPα/CD47 plays an important role in regulation of tumor immune escape. However, the mechanism of CD47 ubiquitination on tumor immune escape remains unclear. Here it is found that TRAF2 bound to the C-terminal of CD47 cytoplasmic fragment and induced its ubiquitination, leading to inhibition of CD47 autophagic degradation by disrupting its binding to LC3, which in turn inhibited macrophage phagocytosis and promoted tumor immune escape. In contrast, loss of TRAF2 facilitated CD47 autophagic degradation and inhibited tumor immune escape. Moreover, autophagy induction promoted CD47 degradation and enhanced the efficacy of CD47 antibody anti-tumor immunotherapy. These findings revealed a novel mechanism of ubiquitination of CD47 on tumor immune escape.
除了PD-1/PD-L1的适应性免疫检查点外，先天性免疫检查点信号调节蛋白α（SIRPα）/信号调节蛋白CD47在肿瘤免疫逃逸的调控中也起着重要作用。然而，CD47泛素化在肿瘤免疫逃逸中的机制仍不清楚。本文发现，肿瘤坏死因子受体相关因子2（TRAF2）与CD47细胞质片段的C末端结合并诱导其泛素化，通过破坏其与微管相关蛋白1轻链3（LC3）的结合来抑制CD47的自噬降解，进而抑制巨噬细胞吞噬作用并促进肿瘤免疫逃逸。相反，TRAF2缺失促进了CD47的自噬降解并抑制了肿瘤免疫逃逸。此外，自噬诱导促进了CD47的降解并增强了CD47抗体抗肿瘤免疫治疗的疗效。这些发现揭示了CD47泛素化在肿瘤免疫逃逸中的一种新机制。
