The Hodgkin Lymphoma Microenvironment: Insights from Spatial Transcriptomics.

Classical Hodgkin lymphoma (cHL) is a paradigmatic example of a malignancy in which the tumor microenvironment (TME) plays a dominant role in disease biology. Malignant Hodgkin and Reed-Sternberg (HRS) cells typically constitute only a small minority of the tumor mass (approximately 1-5%). HRS cells are embedded within a complex, highly structured immune and stromal milieu that drives survival, immune evasion, and therapy response. Over the past decade, transcriptomic approaches, particularly single-cell RNA sequencing, have reshaped our understanding of cellular heterogeneity within cHL. However, these approaches lack spatial context, a limitation that is especially relevant in cHL, where cell-cell interactions and physical proximity are central to immune evasion and tumor support. Recent advances in spatial transcriptomics now enable genome-scale, spatially resolved interrogation of gene expression in situ. In this review, we summarize spatially resolved studies of the cHL microenvironment, discuss what they reveal about HRS-centered cellular niches and immune evasion, and highlight how these findings may inform risk stratification, biomarker discovery and microenvironment-directed therapies.