Rationale: STING is a critical player in the innate and adaptive immune system, sensing cytosolic DNA to activate the expression of interferon genes and regulate T lymphocytes, which drives immunogenic responses to cancer cells. Tumor-associated macrophages (TAMs), abundantly present in the tumor microenvironment, play a key role in cancer development. Gastric cancer is one of the most common and leading causes in cancer-related death worldwide. However, studies on the function and regulation of STING in TAMs and their roles in gastric cancer progression are still limited.

Methods: We analyzed STING and CD68 expression of 200 pairs of gastric cancer and adjacent normal tissues by immunohistochemistry to identify the prognostic values of STING, as well as the correlations between STING and CD68 in gastric cancer. The characteristics of STING-altered macrophages, as well as their effects on cancer cell apoptosis and T cell differentiation were examined by flow cytometry. Cytokines secreted by STING-altered macrophages were identified by the Human Inflammation Array3 kit. Concentrations of soluble IL24 and IFN-β were measured by ELISA. In vivo models, including spontaneous gastric cancer in p53^+/- mice and cell line-based xenografts, were established, and clinical benefits of STING-altered macrophages were examined.

Results: Our study identifies STING as a prognostic factor for gastric cancer, and for the first time demonstrated that knocking-down STING and STING activation by 2'3'-c-GAMP both promote TAMs polarizing into pro-inflammatory subtype and induce apoptosis of gastric cancer cells, mechanistically through IL6R-JAK-IL24 pathway.

Conclusions: This study evaluated effects of targeting STING in TAMs in anti-gastric-cancer therapies. Moreover, we unveil a novel function of STING to activate the IL6R-JAK-IL24 pathway in macrophages.

原理： STING是先天性和适应性免疫系统的关键角色，可感知胞质DNA激活干扰素基因的表达并调节T淋巴细胞，从而驱动对癌细胞的免疫原性应答。在肿瘤微环境中大量存在的肿瘤相关巨噬细胞（TAM）在癌症发展中起关键作用。胃癌是全世界与癌症相关的死亡中最常见和最主要的原因之一。然而，关于TAM中STING的功能和调节及其在胃癌进展中的作用的研究仍然有限。

方法：我们采用免疫组织化学方法分析了200对胃癌及癌旁正常组织中STING和CD68的表达，以鉴定STING的预后价值以及STING和CD68在胃癌中的相关性。通过流式细胞术检查了STING改变的巨噬细胞的特征，以及它们对癌细胞凋亡和T细胞分化的影响。由STING改变的巨噬细胞分泌的细胞因子通过Human Inflammation Array3试剂盒进行鉴定。通过ELISA测量可溶性IL24和IFN-β的浓度。建立了体内模型，包括p53 ^+/-小鼠中的自发性胃癌和基于细胞系的异种移植物，并检查了STING改变的巨噬细胞的临床益处。

结果：我们的研究将STING鉴定为胃癌的预后因素，并首次证明敲低STING和2'3'-c-GAMP激活STING均可促进TAM极化为促炎亚型并诱导TAM凋亡。胃癌细胞，通过IL6R-JAK-IL24途径机械地进行。

结论：本研究评估了靶向TAM中的STING在抗胃癌治疗中的作用。此外，我们揭示了STING的新功能，以激活巨噬细胞中的IL6R-JAK-IL24途径。