Fig. 3.

Interplay between cancer cells and NK cells during tumorigenesis. The interaction between tumor cells and NK cells changes continuously with NK cell development, tumor progression and metastasis. During the stage of tumorigenesis (a), NK cells recognize tumor cells through various surface molecules and switch to the active status. In the immune control stage (b), NK cells exert killing effects by ADCC, secreting cytokines and generating memory NK cells. Meanwhile, changes in the surface molecules of tumor cells also promote anti-tumor metabolic responses. However, long-term exposure of NK cells to tumor cells, tumor- derived molecules and tumor-educated stromal cells, including fibroblast, monocyte and macrophage, causes NK cells to be in an immunosuppressive state, thereby promoting tumor immune escape and metastasis (c). MHC- I, major histocompatibility complex-I; MICA, MHC class I polypeptide-related sequence A; MICB, MHC class I polypeptide-related sequence B; NCR, natural cytotoxicity receptor; Nfil3, nuclear factor interleukin-3-regulated protein; Id2, inhibitor of DNA binding 2; Tox, thymocyte selection associated high mobility group box; EOMES, eomesodermin; T-bet, T-box transcription factor 21; ADCC, antibody-dependent cell-mediated cytotoxicity; GM-CSF, granulocyte-macrophage colony stimulating factor; PRF1, perforin 1; GZMB, granzyme B; PD-L1, programmed cell death ligand 1; PGE-2, prostaglandin E2; HCC, Hepatocellular Carcinoma; IFN, interfron; TNFα, Tumor Necrosis Factor α;PI3K, Class IA phosphatidylinositol 3 kinase