Unleashing Anti-Tumor Activity of Natural Killer Cells Via Modulation of Immune Checkpoints Receptors and Molecules

Abstract

As vital innate lymphocytes, natural killer (NK) cells suppress cancer progression chiefly by inducing cell lysis and secreting pro-inflammatory cytokines. NK cell activation relies on the balance between inhibitory and stimulating signals mediated by a wide range of surface receptors. Specific receptors initiate intracellular signaling pathways, which are negatively regulated by specific checkpoint molecules. Synergistic activation is controlled by Cbl proteins and GSK-3β, while the downstream signaling pathways induced by ITIM-bearing receptors are regulated by SHP-1. These intracellular NK checkpoints are attractive targets for immune checkpoint blockade therapies, but not enough attention has been given. Hence, this paper discusses the major signaling pathways regulated by the intracellular checkpoints and their potential clinical application. The current progress in the investigation of NK checkpoint receptors is also summarized. This paper aims to promote the development of novel immunotherapies that optimize the tumor-suppressive activity of NK cells while suppressing tumor immunological evasion.