Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis.
Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis.
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STAT3的靶向抑制通过糖酵解诱导肝细胞癌细胞的免疫原性细胞死亡。
DOI：
10.1002/1878-0261.13263
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发表时间：
2022-08
影响因子：
6.6
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Li, Ya;Song, Zhenwei;Han, Qiuju;Zhao, Huajun;Pan, Zhaoyi;Lei, Zhengyang;Zhang, Jian
在肝细胞癌（HCC）中，信号转导和转录激活因子3（STAT 3）处于过度活跃状态，与肿瘤发展和免疫逃逸密切相关。STAT 3抑制重塑肿瘤免疫微环境，但其潜在机制尚未完全阐明。我们发现，STAT 3抑制可以诱导免疫原性细胞死亡（ICD）的HCC细胞通过易位的“吃我”分子钙网蛋白的细胞表面和显着减少的“不吃我”分子白细胞表面抗原CD 47的表达。STAT 3抑制促进树突状细胞（DC）活化，增强巨噬细胞对HCC细胞的识别和吞噬。此外，STAT 3抑制阻止了关键糖酵解酶的表达，促进了HCC中ICD的诱导。有趣的是，STAT 3直接调节CD 47和溶质载体家族2成员1（SLC 2A 1;也称为GLUT 1）的转录。在皮下和原位移植小鼠肿瘤模型中，STAT 3抑制剂napabucasin可预防肿瘤生长，并诱导钙网蛋白和蛋白质二硫键异构酶家族A成员3（PDIA 3;也称为ERp 57）的表达，但抑制CD 47和GLUT 1的表达。同时，肿瘤浸润的DC和巨噬细胞的数量增加，沿着共刺激分子的表达。更多的CD 4+和CD 8 + T细胞聚集在肿瘤组织中，并且CD 8 + T细胞具有较低的检查点分子表达，如淋巴细胞活化基因3蛋白（LAG-3）和程序性细胞死亡蛋白1（PD-1）。值得注意的是，靶向STAT 3的治疗诱导了抗肿瘤免疫记忆应答。这些发现为靶向HCC中STAT 3诱导的ICD提供了一种新的机制，并证实STAT 3是通过重塑肿瘤免疫微环境治疗HCC的潜在靶点。STAT 3抑制通过“吃我”分子钙网蛋白易位至细胞表面和“不吃我”分子CD 47暴露的显著减少诱导HCC细胞的免疫原性细胞死亡（ICD）。STAT 3抑制阻止了关键糖酵解酶的表达，促进了HCC中ICD的诱导。值得注意的是，靶向STAT 3的治疗诱导了抗肿瘤免疫记忆应答。
In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the “eat me” molecule calreticulin to the cell surface and a significant reduction in the expression of the “don’t eat me” molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour‐infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG‐3) and programmed cell death protein 1 (PD‐1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3‐induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment. STAT3 inhibition induces immunogenic cell death (ICD) of HCC cells via translocation of the “eat me” molecule calreticulin to the cell surface and a significant reduction in exposure of the “don’t eat me” molecule CD47. STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Significantly, the antitumour immune memory response was induced by treatment targeting STAT3.
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