Immunotherapy has revolutionized cancer treatment by improving patient outcomes across various cancer indications, yet some approaches, like high-dose recombinant IL-2 therapy, have been limited by severe systemic toxicities. This study introduced a novel strategy to harness the anti-tumor potential of IL-2/15 signaling while avoiding the liabilities, by using a pair of bispecific antibodies, where the first antibody binds to the IL-2/15 receptor subunit β (CD122) and a tumor-associated antigen, and the second antibody binds to the IL-2/15 receptor subunit γ (CD132) and the same or a different tumor-associated antigen. The bispecific antibody pair only activates IL-2/15 signaling in the presence of the tumor associated antigen(s) and thus restricts signaling to the tumor microenvironment.