Background: Natural killer (NK) cells may be used in immunotherapy to treat various cancers, according to recent studies. They play crucial roles in tumor surveillance and control. As a result, the functions of immunological checkpoint molecules and receptors in the control of NK cell function as well as their potential use in tumor immunotherapy is the main objective of this systematic review. Methods: Nine databases (PubMed, Scopus, Google Scholar, Cochrane Library, Magiran, SID, Medline, Embase, and Lilacs) were searched for published articles on Potential targets for cancer immunotherapy in natural killer cells\\\' immune checkpoint molecules from January 2016 to December 2022. Twenty-five affiliated articles with complete abstracts were included in this study. All data were extracted from interconnected papers and analyzed with R version 4.2.1 artificial intelligence software. Results: Human NK cells are crucial and play a vital role in the development of cancer therapeutics. In the presence of the tumor microenvironment, NK cells transform into dysfunctional cells with increased expression of inhibitory immune checkpoints, such as the non- HLA-class I-specific inhibitory receptors PD-1, TIGIT, CD112R, CD96, IL-1R8, and TIM-3, and decreased expression of activating receptors (such as NKG2D and CD226). A novel inhibitory immunological checkpoint route in NK cells is adenosine-A2AR signaling. The anticancer activity of NK cells can be restored by blocking these inhibitory checkpoint molecules with immune receptor inhibitors and activating co-stimulatory receptor signaling by boosting co-stimulatory receptor expression. Conclusion: Many primary studies have been conducted and are still being conducted at various stages of the clinical process to support the efficacy of NK cell-targeted immunotherapies based on immune checkpoint molecules in NK cells. The safety, tolerability, and therapeutic effectiveness of medications that target these checkpoints as well as their combination therapy require additional study.

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