Here, we evaluated for the first time, (1) the immunomodulatory effect of IL-15SA/IL-15RαSu-Fc on the subpopulations of NK cells (and memory CD8+ T cells) and (2) its anti-tumor activity against pulmonary metastases in the 4T1 breast and CT26 colon carcinoma models, with the aim of providing a rationale for the utilization of IL-15SA/IL-15RαSu-Fc, especially in combination with checkpoint inhibitors, in the immunotherapy of highly metastatic cancers. The gene discussed is CD8A; the disease is colon carcinoma.