Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity
Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity
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DOI：
10.1016/j.canlet.2022.215880
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发表时间：
2022-08-18
期刊：
影响因子：
9.7
通讯作者：
Zhang，Jian
中科院分区：
文献类型：
--
作者：
Wang，Xueyao;Hu，Rui;Zhang，Jian
索拉非尼是晚期肝细胞癌（HCC）的一线治疗药物。然而，使用单药化疗难以缓解这种疾病过程。晚期HCC的联合治疗已成为主要趋势。由于STAT 3过表达参与了肝癌细胞的化疗耐药和免疫逃逸，近年来它已成为肝癌潜在的治疗靶点。GEO数据库分析显示，来自索拉非尼无应答者的肿瘤组织中的STAT 3水平显著高于索拉非尼应答者。我们的研究表明，STAT 3敲低促进索拉非尼诱导的ER应激诱导的细胞凋亡。重要的是，死亡HCC细胞释放的DNA刺激了CD 103 + DC中的cGAS-STING信号通路，并促进了I型干扰素的产生，从而增强了CD 8 +T细胞和NK细胞的抗肿瘤功能。总之，我们的研究结果表明，索拉非尼和STAT 3敲低的组合策略可能是一种潜在的HCC治疗策略，直接有效地干扰HCC细胞的肿瘤特征，同时通过DC的cGAS-STING-I型IFN轴改善肿瘤微环境，诱导抗HCC免疫应答。
Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). However, it is difficult to alleviate this disease process using single-agent chemotherapy. Using combination therapies for advanced HCC has become a major trend. Given that STAT3 overexpression is involved in chemotherapy resistance and the immune escape of HCC cells, it has become a potential therapeutic target for HCC in recent years. GEO database analysis showed that STAT3 levels in tumor tissues from non-responders were significantly higher than those in responders to sorafenib. Our studies demonstrated that STAT3 knockdown promoted sorafenib-induced ER stress-induced apoptosis. Importantly, the DNA released by dead HCC cells stimulated the cGAS-STING signaling pathway in CD103+DCs and promoted type I interferon production, thus, enhancing the anti-tumor function of CD8+T and NK cells. In conclusion, our results revealed that the combination strategy of sorafenib and STAT3 knockdown might be a potential treatment strategy for HCC, directly and efficiently disturbing the tumor features of HCC cells while improving the tumor microenvironment via the cGAS-STING-Type I IFNs axis of DCs, inducing anti-HCC immune responses.