Histone variants are incorporated and exchanged at specific regions of the genome to regulate homeostasis and cellular identity. As such, histone variant dysfunction has profound consequences for tumor cells; however, the role of these chromatin components in the tumor microenvironment (TME) remains unclear. Using an autochthonous, immunocompetent primary melanoma model, Dan showed that mice devoid of the histone variant macroH2A develop larger tumors, underpinning a compromised anti-tumor immune response. This stems from intrinsic upregulation of inflammatory genes in cancer-associated fibroblasts (CAFs), where macroH2A deficiency leads to rewiring of 3D chromatin interactions. Dan is using his expertise with in vivo tumor models, in vitro cell biology, various modalities of large-scale data analysis (e.g., single cell RNA-seq, spatial transcriptomics, and epigenomics), and distinct compartments of the TME, to define how epigenetic modulation of CAFs directs their phenotype, in turn affecting immune cell activity in melanoma.