The IL-2 receptor (IL-2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Tregs) and anti-tumor T cells. Here we used IL-2Rβ-selective IL-2/anti-IL-2 complexes (IL-2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer (OC) model. Despite strong tumor rejection, IL-2c unexpectedly lowered the tumor microenvironmental CD8+/Treg ratio. IL-2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL-2c also reduced Treg-mediated, high-affinity IL-2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T cell IL-2R signaling was simultaneously improved, suggesting that IL-2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL-2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL-2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL-2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments.Copyright ©2020, American Association for Cancer Research.