Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B cells and bore transcriptional hallmarks of activation and effector function, suggesting that they may be primed for anti-tumor immunity. Spatial characterization of the DLBCL immune microenvironment, therefore, reveals cellular niches that foster divergent patterns of cell-cell interactions contributing to the phenotypic heterogeneity of both niche-resident tumor and immune cells.
© 2025. The Author(s).