Figure 4.

Future therapeutic strategies are based on adaptive NK cells. (A) When the CD16 pathway is activated by Abs or NKCEs binding to different targets, adaptive NK cells secrete numerous IFN-γ and TNF-α to regulate anti-tumor immunity; (B) Methods to significantly improve the efficiency of ADCC can be considered from two aspects of adaptive NK cells and target cells, such as avoiding CD16 on the surface of adaptive NK cells being cleaved by ADAM17 or MMP, enhancing its binding with Fc segment in a high-affinity manner, and advancing Ag presentation to the surface of tumor cells to reduce endocytosis; (C) Adding 4-1BB/CD28 and CD3ζ co-stimulatory signals to adaptive NK cells, or blocking the co-inhibitory pathway with the antagonistic Ab EOS-448 of TIGIT, and stimulating the co-activation pathway of CD2, NKG2C, and 4-1BB with agonist are all effective means to strengthen adaptive NK cell function; (D) Up-regulation of ARID5B expressed in adaptive NK cells can alter its metabolic characteristics, resulting in longer persistence and increased function. NKCEs, NK cell engagers; ADCC, Ab-dependent cell-mediated cytotoxicity; ADAM17, A disintegrin and metalloproteinase-17; and MMP, Matrix Metalloproteinase.