索拉非尼联合 STAT3 敲低触发 ER 应激诱导的 HCC 凋亡和 cGAS-STING 介导的抗肿瘤免疫

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.