Combined BRAF, MEK, and CDK4/6 inhibition is an emerging therapy for the treatment of BRAF^V600E melanoma, but the immunomodulatory effects of this combination remain unexplored. Using flow cytometry and single-cell RNA sequencing, Lelliott et al. show that the triple therapy markedly alters the tumor immune microenvironment in a mouse model of BRAF^V600E melanoma. Specifically, this combination therapy promotes high levels of lymphocyte infiltration but simultaneously depletes immune-potentiating myeloid subsets, including proinflammatory macrophages and CD103⁺ dendritic cells (DC). This lowered frequency of CD103⁺ DCs correlates with resistance to immune checkpoint blockade (ICB) in mice and poor responses to ICB in patients. The study has implications for clinical trial design, as it highlights that, despite potent tumor-intrinsic effects, this triple therapy may adversely impact antitumor immunity. Read more in this issue on page 136. Original image from Fig. 1I. Artwork by Lewis Long.