The Rise of NK Cell Checkpoints as Promising Therapeutic Targets in Cancer Immunotherapy

Checkpoint immunotherapy that targets inhibitory receptors of T cells, thereby reversing the functional exhaustion of T cells, marks a breakthrough in anticancer therapy. The success of T cell-directed checkpoint inhibitors of CTLA-4 and PD-1/PD-L1 has opened a new approach for cancer immunotherapy and resulted in extensive research on immune checkpoints. However, it is only in recent years that research on NK cell exhaustion and potential checkpoints impacting NK cells has become popular. NK cells, as the major player in innate immunity, are critical for immune surveillance, particularly the control of metastasis and hematological cancers. The balance between activating and inhibitory signals fine tunes the activation and effector functions of NK cells, and transformed cells modulate NK cells by upregulating negative signaling that "exhausts" NK cells. Exhausted NK cells with excessive expression of inhibitory receptors (checkpoint molecules) are impaired in the recognition of tumor cells as well as antitumor cytotoxicity and cytokine secretion. Therefore, an understanding of the potential checkpoint molecules involved in NK cell exhaustion is particularly important in terms of NK cell-targeted cancer immunotherapy. In this review, we summarize recent advances in NK cell checkpoint inhibitors and their progress in clinical trials. Moreover, we highlight some of the latest findings in fundamental NK cell receptor biology and propose potential NK cell checkpoint molecules for future immunotherapeutic applications.