Melanoma brain metastasis (MBM) is associated with poor prognosis. In this issue of Cancer Cell, Rodriguez-Baena et al. identify nuclear factor κB (NF-κB) (Rela) as a driver of pro-tumoral microglia in MBM. While Rela deletion reprograms microglia, enhancing proinflammatory and anti-metastasis T cell responses, RELA activation in human macrophages correlates with immunotherapy resistance.