The use of BRAF and MEK inhibitors (BRAF/MEKi) as a targeted therapy approach has redefined treatment and outcomes for BRAF-mutant melanoma. Despite its success, the emergence of drug-tolerant minimal residual disease (MRD) frequently culminates in therapeutic resistance, limiting long-term outcomes. Harnessing the innate immune system, particularly natural killer (NK) cells, represents a promising avenue to eliminate these residual cancer cells. This proposal addresses the critical need for strategies that prevent melanoma relapse during MRD by harnessing the cytotoxic potential of cytokine-induced memory-like (CIML) natural killer (NK) cells. CIML NK cells, primed via IL-12, IL-18, and IL-15 stimulation, exhibit enhanced effector functions, positioning them as a robust tool for eliminating residual melanoma cells7. We hypothesize that CIML NK cells will synergize with BRAF/MEKi therapy to eradicate melanoma cells during tumor regression, thereby eliminating or reducing MRD burden, preventing resistance and extending remission. This hypothesis will be tested through two aims. First, we will evaluate the therapeutic efficacy of adoptively transferred CIML NK cells during both tumor regression and MRD in BRAF/MEKi-treated murine melanoma models. Second, we will define the direct effects of BRAF/MEKi on CIML NK cell proliferation, cytokine production, and migration, including the potential for synergy with anti-PD-L1 treatment. The findings from this study will provide mechanistic insights into NK cell-mediated tumor control and highlight a rational, translational approach for enhancing melanoma therapy by integrating innate immunity with targeted treatments.