HER2信号通路可能参与了胃癌（GC）肿瘤微环境（TME）中免疫细胞活化的调控。然而，HER2状态与HER2阳性GC TME中免疫细胞状况之间的关系尚不清楚。为了研究HER2信号对环状GMP-AMP合酶（cGAS）-干扰素基因刺激剂（STING）通路的影响，该通路对GC TME中免疫细胞活化起贡献，我们通过考虑HER2阳性GC组织中的HER2异质性，评估了HER2、cGAS-STING的表达与CD8+肿瘤浸润淋巴细胞（TIL）数量之间的关联。我们还使用人类HER2阳性GC细胞系在体外检查了HER2信号对STING信号的激活效应。 HER2在HER2阳性GC组织中的表达具有高度的异质性，我们发现在HER2阳性GC组织中，CD8+TIL在HER2高表达区域明显低于HER2低表达区域。有趣的是，肿瘤细胞内部的STING表达（而不是cGAS）在HER2高表达区域明显低于HER2低表达区域。此外，通过体外实验，我们证明了HER2信号阻断会增加HER2阳性GC细胞系中STING及其靶基因（包括IFNB1，CXCL9/10/11和CCL5）的表达。我们的结果表明HER2信号可能通过抑制HER2阳性GC肿瘤细胞中的STING信号来抑制GC TME中的免疫细胞活化。© 2023年。作者受国际胃癌学会和日本胃癌学会的独家许可。

HER2 signaling might be involved in the regulation of immune cell activation in the tumor microenvironment (TME) of gastric cancer (GC). However, the relationship between HER2 status and immune cell condition in the HER2-positive GC TME is not clearly understood.To investigate the effect of HER2 signaling on the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contributes to immune cell activation in the GC TME, we evaluated the associations among the expressions of HER2, cGAS-STING, and the number of CD8+ tumor-infiltrating lymphocytes (TIL) by considering HER2 heterogeneity in HER2-positive GC tissues. We also examined the effect of HER2 signaling on the activation of STING signaling in vitro using human HER2-positive GC cell lines.The expression of HER2 is highly heterogeneous in HER2-positive GC tissues, and we found that the number of CD8+ TIL in HER2 high areas was significantly lower than that in HER2 low areas in HER2-positive GC tissues. Intriguingly, the tumor cell-intrinsic expression of STING, but not cGAS, was also significantly lower in the HER2 high areas than the HER2 low areas in HER2-positive GC tissues. Moreover, in vitro experiments, we demonstrated that the blockade of HER2 signaling increased the expression of STING and its target genes, including IFNB1, CXCL9/10/11, and CCL5, in HER2-positive GC cell lines.Our results suggest that HER2 signaling might suppress immune cell activation in the GC TME by inhibiting STING signaling in tumor cells in HER2-positive GC.© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.