Most immunotherapy efforts aim to mobilize CD8+ T cells against cancer cells. Many tumors lack many neoantigens, and others are selected for partial or complete loss of MHC I, even before immunotherapy intervention. Checkpoint immunotherapy further exacerbates this problem as it preferentially amplifies CD8 cytotoxic effector cell activity, which targets MHC I presented tumor epitopes, imposing strong selection for loss of MHC I or other antigen presentation functions. Our work focuses on mobilizing NK cells and CD4 T cells to attack tumors. Innate immune system agonists and engineered cytokines synergize in eliciting such responses. I will discuss the impact and mechanisms underlying this approach, as examined in mouse cancer models, and its potential for preventing acquired resistance to checkpoint immunotherapy.