A Single-Cell Analysis of the NK-Cell Landscape Reveals That Dietary Restriction Boosts NK-Cell Antitumor Immunity via Eomesodermin

Abstract Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cells, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. NK cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. In this study, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. First, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through nontumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.