1. Academic Validation
  2. 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

  • Cancer Lett. 2022 Oct 28;547:215880. doi: 10.1016/j.canlet.2022.215880.
Xueyao Wang 1 Rui Hu 1 Zhenwei Song 1 Huajun Zhao 1 Zhaoyi Pan 1 Yujie Feng 1 Yating Yu 1 Qiuju Han 1 Jian Zhang 2
Affiliations

Affiliations

  • 1 Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
  • 2 Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China. Electronic address: zhangj65@sdu.edu.cn.
Abstract

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.

Keywords

CD103(+) DCs; ER stress; PKR; STING; cGAS; p-eIF2α.

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