Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.

转移是癌症相关死亡的主要原因，其中肺部是最常受影响的器官。我们发现，肺驻留 2 类先天淋巴细胞 (ILC2) 的激活精心策划了对自然杀伤 (NK) 细胞介导的先天抗肿瘤免疫的抑制，导致肺转移和死亡率增加。使用多种肺转移模型，我们发现肺中白细胞介素 (IL)-33 依赖性 ILC2 激活主要参与促进肿瘤负荷。 ILC2 驱动的先天 2 型炎症伴随着干扰素 γ 产生和肺 NK 细胞细胞毒功能的深度局部抑制。 ILC2 依赖性 NK 细胞抑制是通过先天调节机制来阐述的，该机制依赖于 IL-5 诱导的肺嗜酸性粒细胞增多，最终限制 NK 细胞的代谢适应性。 IL-33 或 IL-5 的治疗靶向可逆转 NK 细胞抑制并减轻癌症负担。因此，我们揭示了 IL-33 和 ILC2 通过抑制先天 1 型免疫的能力来促进肿瘤转移的重要功能。