作为肿瘤微环境（TME）中主要的免疫抑制成分，癌症相关成纤维细胞（CAF）抑制自然杀伤细胞（NK细胞）活性，促进肿瘤进展和免疫逃逸；然而，胃癌 (GC) 中 CAF 和 NK 细胞之间的交互机制仍知之甚少。在这项研究中，我们证明 NK 细胞水平与人类 GC 中 CAF 丰度呈负相关。 CAF 通过诱导铁死亡（一种以铁依赖性脂质过氧化物积累为特征的细胞死亡过程）来损害 NK 细胞的抗肿瘤能力。 CAFs 通过促进铁过载诱导 NK 细胞铁死亡；相反，细胞内铁水平降低可保护 NK 细胞免受 CAF 诱导的铁死亡。从机制上讲，CAF 通过将铁输出到 TME 来增加 NK 细胞内的不稳定铁库，这是由 CAF 中铁调节基因 Ferroportin1 和 hephaestin 表达上调介导的。此外，CAF衍生的卵泡抑素样蛋白1（FSTL1）通过DIP2A-P38途径上调NK细胞中NCOA4的表达，并且NCOA4介导的铁蛋白自噬是CAF诱导的NK细胞铁死亡所必需的。在人类患者衍生的类器官模型中，使用去铁胺和 FSTL1 中和抗体的组合对 CAF 进行功能性靶向，可显着减轻 CAF 诱导的 NK 细胞铁死亡，并增强 NK 细胞对 GC 的细胞毒性。这项研究展示了 TME 中 CAF 抑制 NK 细胞活性的新机制，并提出了一种潜在的治疗方法，以增强 NK 细胞介导的针对 GC 的免疫反应。版权所有 © 2023 作者。由 Elsevier B.V. 出版。保留所有权利。

As the predominant immunosuppressive component within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) inhibit Natural Killer cell (NK cell) activity to promote tumor progression and immune escape; however, the mechanisms of cross-talk between CAFs and NK cells in gastric cancer (GC) remain poorly understood. In this study, we demonstrate that NK cell levels are inversely correlated with CAFs abundance in human GC. CAFs impair the anti-tumor capacity of NK cells by inducing ferroptosis, a cell death process characterized by the accumulation of iron-dependent lipid peroxides. CAFs induce ferroptosis in NK cells by promoting iron overload; conversely, decreased intracellular iron levels protect NK cells against CAF-induced ferroptosis. Mechanistically, CAFs increase the labile iron pool within NK cells via iron export into the TME, which is mediated by the upregulated expression of iron regulatory genes ferroportin1 and hephaestin in CAFs. Moreover, CAF-derived follistatin like protein 1(FSTL1) upregulates NCOA4 expression in NK cells via the DIP2A-P38 pathway, and NCOA4-mediated ferritinophagy is required for CAF-induced NK cell ferroptosis. In a human patient-derived organoid model, functional targeting of CAFs using a combination of deferoxamine and FSTL1-neutralizing antibody significantly alleviate CAF-induced NK cell ferroptosis and boost the cytotoxicity of NK cells against GC. This study demonstrates a novel mechanism of suppression of NK cell activity by CAFs in the TME and presents a potential therapeutic approach to augment the immune response against GC mediated by NK cells.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.