Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity

• Published in: Cancer letters 2022-10, Vol.547, p.215880-215880, Article 215880
• Main Authors: Wang, Xueyao, Hu, Rui, Song, Zhenwei, Zhao, Huajun, Pan, Zhaoyi, Feng, Yujie, Yu, Yating, Han, Qiuju, Zhang, Jian
• Format: Article
• Language: English
• Subjects: Ablation; Amino acids; Angiogenesis; Antibodies; Antigens; Antitumor activity; Apoptosis; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; CD103 antigen; CD103+ DCs; CD8 antigen; Cell Line, Tumor; cGAS; Chemoresistance; Chemotherapy; Drug resistance; Endoplasmic Reticulum Stress; ER stress; Experiments; Hepatitis B; Hepatitis C; Hepatocellular carcinoma; Humans; Immune response; Immunity (Disease); Inhibitor drugs; Interferon; Kinases; Laboratory animals; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Lymphocytes; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Nucleotidyltransferases - therapeutic use; p-eIF2α; Pathogenesis; Phosphorylation; PKR; Proteins; Signal transduction; Software; Sorafenib - pharmacology; Sorafenib - therapeutic use; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Statistical analysis; STING; Targeted cancer therapy; Therapeutic targets; Tumor Microenvironment; Tumors; Variance analysis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215880

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. •STAT3 levels in tumor tissues from non-responders to sorafenib were significantly high.•A low sorafenib dose combined with STAT3 knockdown showed excellent anti-HCC activity.•STAT3 knockdown promoted sorafenib-induced ER stress-induced apoptosis.•HCC cells treated with sorafenib and sh-STAT3 activated the cGAS-STING-Type I IFNs signaling pathway in CD103+DCs.