Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy

Simple Summary Immune checkpoint blockade (ICB) with antibodies targeting CTLA-4 (Cytotoxic Lymphocyte Antigen 4) and/or programmed death-1 protein (PD-1)/programmed death ligand-1 (PD-L1) has significantly modified the therapeutic landscape of a broad range of human tumor types, including advanced non-small-cell lung cancer (NSCLC). Despite great advances of checkpoint immunotherapies, a minority of NSCLC patients (<20%) respond and/or experience long-term clinical benefits from these treatments. Limited response rates of T cell-based checkpoint immunotherapies suggest the presence of other checkpoints able to inhibit effective anti-tumor immune responses. Natural Killer (NK) cells represent a promising target for tumor immunotherapies, particularly against tumors that escape T-cell-mediated control. Like T cell function, NK cell function is also regulated by inhibitory immune-checkpoint molecules. In this review, we will provide an overview of the rationale, mechanisms of action, and clinical efficacy of these NK cell-based checkpoint therapy approaches. Finally, the future directions and current enhancements planned will be discussed. Immune checkpoint inhibitors (ICIs) immunotherapy has represented a breakthrough in cancer treatment. Clinical use of ICIs has shown an acceptable safety profile and promising antitumor activity. Nevertheless, some patients do not obtain clinical benefits after ICIs therapy. In order to improve and cure an increasing number of patients, the field has moved toward the discovery of new ICIs expressed by cells of innate immunity with an elevated inherent antitumor activity, such as natural killer cells. This review will focus on the recent findings concerning the role of classical and non-classical immune checkpoint molecules and receptors that regulate natural killer cell function, as potential targets, and their future clinical application.