Interleukin-15 (IL-15), a cytokine discovered in 1994, supports the homeostasis of cytotoxic immune cells, exhibits a broad biological activity. IL-15 stimulate the proliferation of activated T cells as well as to facilitate the induction of cytotoxic T-lymphocytes (like CD8+), and the generation, proliferation, and activation of NK cells. Therefore, IL-15 is applied to the rapidly expanding cancer immunotherapy field combining with other agents, i.e., checkpoint inhibitors, monoclonal antibodies, chemotherapy, radiation, and chimeric antigen receptor T (CAR-T) cells, in order to target multiple mechanisms and enhance the immune response against tumors, which provides advantages to control and treat cancers.