Polyclonal metastases frequently arise from clusters of circulating tumor cells (CTCs). CTC clusters metastasize better than single CTCs, but the underlying molecular mechanisms are poorly understood. Here, we show that polyclonal metastatic seeds exhibit higher resistance to natural killer (NK) cell killing. Using breast cancer models, we observed higher proportions of polyclonal lung metastasis in immunocompetent mice compared with mice lacking NK cells. Depleting NK cells selectively increased monoclonal but not polyclonal metastases, suggesting that CTC clusters are less sensitive to NK-mediated suppression. Transcriptional analyses revealed that clusters have elevated expression of cell–cell adhesion and epithelial genes, which is associated with decreased expression of NK cell activating ligands. Furthermore, perturbing tumor cell epithelial status altered NK ligand expression and sensitivity to NK-mediated killing. Collectively, our findings show that NK cells can determine the fate of CTCs of different epithelial and mesenchymal states, and impact metastatic clonal evolution by favoring polyclonal seeding.

多克隆转移通常由循环肿瘤细胞 (CTC) 簇引起。 CTC 簇比单个 CTC 转移得更好，但其潜在的分子机制尚不清楚。在这里，我们证明多克隆转移种子对自然杀伤（NK）细胞杀伤表现出更高的抵抗力。使用乳腺癌模型，我们观察到与缺乏 NK 细胞的小鼠相比，免疫功能正常的小鼠中多克隆肺转移的比例更高。耗尽 NK 细胞会选择性地增加单克隆转移，但不会增加多克隆转移，这表明 CTC 簇对 NK 介导的抑制不太敏感。转录分析显示，簇的细胞间粘附和上皮基因的表达升高，这与 NK 细胞激活配体的表达降低有关。此外，扰乱肿瘤细胞上皮状态会改变 NK 配体表达和对 NK 介导杀伤的敏感性。总的来说，我们的研究结果表明，NK 细胞可以决定不同上皮和间质状态的 CTC 的命运，并通过有利于多克隆接种来影响转移性克隆进化。