Interleukin-15 (IL-15) is a common γ-chain cytokine that plays a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha chain that are together termed heterodimeric IL-15 (hetIL-15). HetIL-15 produced from engineered human cell lines showed favorable pharmacokinetics and bioactivity compared to monomeric IL-15 in both mice and macaques. We investigated the anti-tumor efficacy of hetIL-15, using the MC38 colon carcinoma mouse model. hetIL-15 resulted in a significant delay in tumor growth, when administered intraperitoneally every 2 days for 2 weeks. In addition, intratumoral delivery of hetIL-15 induced regression of established tumors and cured 50% of mice. Tumor-free mice were resistant to tumor challenge, demonstrating the development of specific anti-tumor immune responses. We further dissected the mechanism leading to tumor control in hetIL-15-treated mice, discovering a new interplay between IL-15 and the cognate cytokine interleukin-2 (IL-2). Repeated injections of hetIL-15 resulted in an increased CD8⁺/Treg cells ratio in spleen, lymph nodes and tumor microenvironment. Interestingly, hetIL-15 induced a transient accumulation of CD8⁺ T cells expressing the high affinity IL-2 receptor CD25, that compete with CD25⁺Treg for the available IL-2. In addition, IL-15 decreased the frequency of IL-2-producing CD4⁺ T cells, while increasing their ability to secrete IFNγ. These data suggest that hetIL-15 treatment limits Treg fitness through a concerted action of both CD8⁺ and CD4⁺ T cells, that results in an IL-2 deprived environment. Preclinical cancer studies support the use of hetIL-15 in tumor immunotherapy approaches to promote the development of anti-tumor responses by favoring effector over regulatory cells.