巨噬细胞先天免疫反应在肿瘤发生中起着重要作用。然而，巨噬细胞STING信号通路在调节肿瘤微环境、抑制转移部位肿瘤生长的作用和机制还不太清楚。我们评估了结肠癌（CRC）肝转移患者的肝组织样本中的STING表达情况。通过将小鼠结肠癌细胞（MC38）经脾脏注入到全身或骨髓NOD样受体蛋白3（NLRP3）缺失小鼠和野生型（WT）小鼠的模型中，分离出包括巨噬细胞和自然杀伤（NK）细胞在内的肝非实质细胞进行流式细胞术分析。将MC38预处理的骨髓源性巨噬细胞与脾NK细胞共培养进行体外研究。在相邻和肿瘤组织和肝内巨噬细胞中检测到了明显的STING信号激活。全身或骨髓STING缺陷小鼠表现出CRC肝转移加重、生存期缩短、肝内浸润和NK细胞抗肿瘤功能受损的现象。在野生型动物中去除NK细胞会增加其转移负担，而在骨髓STING缺陷小鼠中则没有显著的作用。STING信号的激活促进了巨噬细胞分泌白细胞介素（IL）-18和IL-1β，通过促进巨噬细胞中4-1BBL和NK细胞中4-1BB的表达优化了NK细胞的抗肿瘤活性。此外，MC38处理激活了巨噬细胞NLRP3信号通路，而STING缺陷能够抑制其活化。骨髓源性NLRP3缺陷加重了肿瘤负担并抑制了NK细胞的激活。NLRP3通过其激动剂的活化，在骨髓SITNG-deficient小鼠中有效抑制了CRC肝转移。我们证明了STING信号通过共刺激信号4-1BBL/4-1BB促进巨噬细胞介导的NLRP3介导的IL-18和IL-1β产生，优化NK细胞的抗肿瘤功能。 ©作者(或其雇主)2023年。在CC BY-NC下允许重新使用。不允许商业再利用。由BMJ出版。

Macrophage innate immune response plays an important role in tumorigenesis. However, the role and mechanism of macrophage STING signaling in modulating tumor microenvironment to suppress tumor growth at secondary sites remains largely unclear.STING expression was assessed in liver samples from patients with colorectal cancer (CRC) liver metastasis. Global or myeloid stimulator of interferon gene (STING)-deficient mice, myeloid NOD-like receptor protein 3 (NLRP3)-deficient mice, and wild-type (WT) mice were subjected to a mouse model of CRC liver metastasis by intrasplenic injection of murine colon carcinoma cells (MC38). Liver non-parenchymal cells including macrophages and natural killer (NK) cells were isolated for flow cytometry analysis. Bone marrow-derived macrophages pretreated with MC38 were co-cultured with splenic NK cells for in vitro studies.Significant activation of STING signaling were detected in adjacent and tumor tissues and intrahepatic macrophages. Global or myeloid STING-deficient mice had exacerbated CRC liver metastasis and shorten survival, with decreased intrahepatic infiltration and impaired antitumor function of NK cells. Depletion of NK cells in WT animals increased their metastatic burden, while no significant effects were observed in myeloid STING-deficient mice. STING activation contributed to the secretion of interleukin (IL)-18 and IL-1β by macrophages, which optimized antitumor activity of NK cells by promoting the expression of 4-1BBL in macrophages and 4-1BB in NK cells, respectively. Moreover, MC38 treatment activated macrophage NLRP3 signaling, which was inhibited by STING depletion. Myeloid NLRP3 deficiency increased tumor burden and suppressed activation of NK cells. NLRP3 activation by its agonist effectively suppressed CRC liver metastasis in myeloid SITNG-deficient mice.We demonstrated that STING signaling promoted NLRP3-mediated IL-18 and IL-1β production of macrophages to optimize the antitumor function of NK cells via the co-stimulation signaling of 4-1BBL/4-1BB.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.