A fundamental hallmark of cancer is that tumor cells repurpose the tissue microenvironment to promote their own survival. An increased understanding of these mechanisms may lead to improved microenvironment-directed therapies, particularly in lymphoid malignancies. In classic Hodgkin lymphoma (cHL), the rare malignant Hodgkin Reed Sternberg (HRS) cells are surrounded by a CD4+ T-cell and macrophage-rich inflammatory infiltrate. Recent multiplexed immunofluorescence studies suggest that the micron-scale niche around HRS cells is composed of distinct populations of PD-L1+ macrophages and CD4+ T cells, including regulatory CTLA4+ and LAG3+ subsets (Carey et al. Blood 2017, Patel et al. Blood 2019 and Aoki et al. Cancer Discov 2020). However, the topography of the intact tumor microenvironment of cHL requires further definition. Recent single-cell RNA sequencing studies have led to important insights into the biology of cHL; however, they do not adequately capture myeloid cells, fibroblasts, and HRS cells, likely due to the relative fragility of these cells in conventional tissue dissociation protocols. In this study, we use tandem single nucleus and spatially resolved RNA sequencing to systematically dissect the pro-tumorigenic cellular niche of cHL to define potentially targetable microenvironmental dependencies