胃癌 (GC) 是一个重大的全球健康问题，GC 中肝转移 (LM) 的发展代表着与患者不良预后相关的关键阶段。在这项研究中，我们采用单细胞 RNA 测序 (scRNA-seq) 来研究 GC 肝转移的免疫景观，揭示肿瘤免疫微环境 (TIM) 中的几种免疫抑制成分。我们的研究结果揭示了癌症相关成纤维细胞 (CAF)、骨髓源性抑制细胞 (MDSC) 样巨噬细胞、肿瘤相关巨噬细胞 (TAM) 样巨噬细胞和初始 T 细胞的存在增加，而传统树突状细胞 (cDC) LM 中效应 CD8 T 细胞下降。此外，我们还发现了两个不同的自然杀伤 (NK) 细胞簇，它们表现出不同的细胞毒性相关基因表达，其中细胞毒性 NK 细胞在 LM 中显着减少。引人注目的是，TGFβ 被确定为 NK 细胞功能障碍的诱导剂，可能导致免疫逃避和肿瘤转移。在临床前LM模型中，抑制TGFβ和转移NK细胞的联合方法表现出协同作用，导致肝转移显着减少。这项工作强调了了解 GC 肝转移中复杂免疫动态的重要性，并提出了一种结合 TGFβ 抑制和基于 NK 的免疫疗法来改善患者预后的有前途的策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Gastric cancer (GC) is a substantial global health concern, and the development of liver metastasis (LM) in GC represents a critical stage linked to unfavorable patient prognoses. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the immune landscape of GC liver metastasis, revealing several immuno-suppressive components within the tumor immune microenvironment (TIM). Our findings unveiled an increased presence of cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cell (MDSC)-like macrophages, tumor-associated macrophage (TAM)-like macrophages, and naive T cells, while conventional dendritic cells (cDCs) and effector CD8 T cells declined in LM. Additionally, we identified two distinct natural killer (NK) cell clusters exhibiting differential cytotoxicity-related gene expression, with cytotoxic NK cells notably reduced in LM. Strikingly, TGFβ was identified as an inducer of NK cell dysfunction, potentially contributing to immune evasion and tumor metastasis. In preclinical LM models, the combined approach of inhibiting TGFβ and transferring NK cells exhibited a synergistic impact, resulting in a significant reduction in liver metastasis. This work highlights the importance of understanding the complex immune dynamics within GC liver metastasis and presents a promising strategy combining TGFβ inhibition and NK-based immunotherapy to improve patient outcomes.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.