STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2
STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2
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DOI：
10.1038/s41556-023-01185-x
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发表时间：
2023-07
影响因子：
21.3
通讯作者：
Liting Zhang;Congqing Jiang;Yunhong Zhong;Kongliang Sun;Huiru Jing;Jiayu Song;Jun Xie;Yaru Zhou;Mao Tian;Chuchu Zhang;Xiaona Sun;Shaowei Wang;Xi Cheng;Yuelan Zhang;Wei Wei-Wei;Xiang Li;Bishi Fu;P. Feng;Bing Wu;H. Shu;Junjie Zhang
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文献类型：
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作者：
Liting Zhang;Congqing Jiang;Yunhong Zhong;Kongliang Sun;Huiru Jing;Jiayu Song;Jun Xie;Yaru Zhou;Mao Tian;Chuchu Zhang;Xiaona Sun;Shaowei Wang;Xi Cheng;Yuelan Zhang;Wei Wei-Wei;Xiang Li;Bishi Fu;P. Feng;Bing Wu;H. Shu;Junjie Zhang
逃避抗肿瘤免疫是癌症的标志。STING是一种假定的先天免疫信号转导适配器，通过协调骨髓细胞中的先天传感和适应性免疫监视在建立抗肿瘤免疫中具有关键作用。STING在各种人类恶性肿瘤中显著沉默，并作为细胞内在的肿瘤抑制因子。STING如何发挥内在的抗肿瘤活性仍不清楚。在这里，我们报告STING限制有氧糖酵解独立于其先天免疫功能。在机制上，STING靶向己糖激酶II（HK2）以阻断其己糖激酶活性。因此，STING抑制HK2以限制肿瘤有氧糖酵解并促进体内抗肿瘤免疫。在人类结直肠癌样本中，乳酸可用作有氧糖酵解的替代物，与STING表达水平和抗肿瘤免疫呈负相关。总之，这项研究表明，STING作为细胞内在的代谢检查点，限制有氧糖酵解，以促进抗肿瘤免疫。这些发现对开发基于STING的治疗方式以改善抗肿瘤免疫疗法具有重要意义。
Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.