The field of cancer research has been significantly propelled by advancements in immunotherapy, including the use of cutting-edge technologies and extensive clinical trials. However, the effectiveness of cell-based immunotherapies, such as CAR-T-cell and natural killer (NK)-cell therapy, for treating solid tumors is limited by the presence of inhibitory tumor microenvironments. Various strategies have been employed to overcome this challenge to enhance cell therapy's functionality. One such approach involves the utilization of stimulatory cytokines to promote the survival of immune cells and counteract the immunosuppressive nature of the tumor microenvironment [1], [2], [3], [4]. Interleukins (ILs), a group of cytokines predominantly produced by leukocytes, play a critical role in the development, differentiation, and function of various immune cells, including NK cells. Over the years, ILs have been extensively investigated for their potential in cancer treatment, with IL-2 being the first FDA-approved immunotherapy for cancer. It plays a crucial role in supporting the survival of NK cells and memory CD8 + T cells. Furthermore, IL-15 can enhance the viability and proliferation of NK cells. In a study conducted by Miller et al., prior administration of immunosuppressive chemotherapy before the introduction of allogeneic NK cells led to the release of IL-15 from the body itself. Furthermore, the levels of IL-15 were found to be directly associated with the in vivo growth of infused NK cells [5]. However, its clinical application has been limited by its short half-life and tight posttranscriptional regulation. To overcome these challenges, efforts have been made to develop IL-15 derivatives, which have been evaluated in clinical trials as monotherapies or in combination with chemotherapy or immune checkpoint inhibitors to enhance their therapeutic potential [1], [6], [7], [8], [9]. This review aims to provide a comprehensive understanding of IL-15′s potential in enhancing NK cell-mediated immunotherapy and its implications for future cancer treatment strategies.