理由：溃疡性结肠炎 (UC) 的治疗提出了持续的临床挑战。新兴研究表明 cGAS-STING 通路促进 UC 的进展，但相互矛盾的结果阻碍了 STING 作为治疗靶点的发展。在本研究中，我们的目标是全面阐明骨髓 STING 在结肠炎和结肠炎相关癌 (CAC) 中的起源、下游信号传导和致病作用。方法：构建 Tmem173 fl/fl Lyz2-Cre ert2 小鼠，用于诱导性骨髓特异性 STING 缺失。采用 RNA 测序、流式细胞术和多重免疫组织化学来研究 DSS 诱导的结肠炎或 AOM/DSS 诱导的癌变中的免疫反应。结肠类器官、原代骨髓来源的巨噬细胞和树突状细胞以及脾 T 细胞用于体外研究。结果：我们观察到，成年小鼠中骨髓 STING 敲除抑制了巨噬细胞成熟，减少了 DC 细胞活化，并抑制了促炎 Th1 和 Th17 细胞，从而预防急性和慢性结肠炎以及 CAC。然而，新生小鼠或肿瘤小鼠中的骨髓 STING 缺失表现出免疫耐受和抗肿瘤免疫力受损。此外，我们发现从受损的结肠类器官而不是细菌产物中释放的 TFAM 相关 mtDNA 以不依赖于细胞外囊泡但依赖于内吞作用的方式激活树突状细胞中的 STING。 IRF3 和 NF-κB 都是 STING 介导的 IL-12 家族细胞因子表达所必需的，可促进 Th1 和 Th17 分化并导致结肠炎的过度炎症。结论：通过骨髓 STING 从受损肠上皮中检测到 TFAM-mtDNA 复合物，通过 IL-12 细胞因子加剧结肠炎，为支持 STING 作为 UC 和 CAC 治疗靶点的发展提供了新的证据。© 作者。

Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.© The author(s).