This study establishes B7-H6 as a therapeutically actionable immune checkpoint in solid malignancies through three principal advances: (1) development of high-affinity bispecific antibodies (BsAbs) redirecting T/NK cells against B7-H6+ tumors, (2) design of a tumor-localized IL-15/IL-15Rα sushi fusion protein to amplify effector cell activity, and (3) identification of NK cell-redirected therapy as the optimal strategy for overcoming immunosuppressive tumor microenvironments (TMEs). The gene discussed is IL15; the disease is neoplasm.