内质网
肝细胞癌
未折叠蛋白反应
细胞生物学
细胞外
CD8型
免疫疗法
基因敲除
肿瘤微环境
免疫原性细胞死亡
生物
免疫系统
癌症研究
免疫学
细胞凋亡
生物化学
作者
Chengdong Liu,Xiaohan Zhou,Hanyi Zeng,Jiaping Yu,Wenwen Li,Wanli Zhang,Yanxia Liao,Haijian Wang,Li Liu
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2024-06-20
卷期号:: OF1-OF18
标识
DOI:10.1158/2326-6066.cir-23-0469
摘要
Endoplasmic reticulum (ER) stress leads to hepatocellular carcinoma (HCC) progression. Small extracellular vesicles (sEVs) play a crucial role in modulating the tumor microenvironment (TME) by influencing cellular communication and immune responses. However, it is unclear whether ER stress modulates the TME through sEVs. In the current study, we investigated the effects and underlying mechanisms of ER stress on the HCC TME. In vivo and in vitro experiments showed that overactivated ER stress was a salient attribute of the immunosuppressive HCC TME. This was caused by the ATF4-promoted release of SNHG6-carrying sEVs, which attenuated T cell-mediated immune responses. Overall, SNHG6 modulated the immunosuppressive TME and aggravated ER stress. Meanwhile, targeting SNHG6 facilitated M1-like macrophage and CD8+ T-cell infiltration and decreased the proportion of M2-like macrophages. In addition, SNHG6 knockdown enhanced anti-PD-1 immunotherapeutic efficacy. Moreover, in HCC patients, overexpression of SNHG6 was associated with a lack of response to anti-PD-1 therapy and poor prognosis, whereas low SNHG6 expression was associated with improved therapeutic efficacy and prognoses. These data indicate that a correlation exists among ER stress, sEVs, an immunosuppressive HCC TME, and immunotherapeutic efficacy. Hence, SNHG6-targeted therapy may represent an effective strategy for patients with HCC.
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