Single cell profiling reveals malignant states and immune landscapes in PCNSL and systemic DLBCL.

Primary central nervous system lymphoma (PCNSL) is a rare, aggressive subtype of diffuse large B-cell lymphoma (DLBCL) with distinct biology. We present the first integrative single-cell transcriptomic atlas comparing PCNSL and systemic DLBCL (sDLBCL), profiling 171,322 cells from 31 patients. We identified five malignant B-cell subtypes with discrete differentiation trajectories. A CNS-enriched progenitor-like B0 subtype with MYC/VEGFA activation predominated in PCNSL and was linked to poor prognosis. PCNSL also exhibited a highly immunosuppressive microenvironment with exhausted cytotoxic T cells, M2-like macrophages, and elevated PD-L1, TIGIT, and BTLA. In contrast, sDLBCL showed more inflammatory signatures. Co-expression network and pharmacogenomic modeling revealed subtype-specific transcriptional modules associated with resistance and outcome. Modules ME7/ME15 were enriched in PCNSL, while ME17 marked drug resistance in sDLBCL. These findings establish PCNSL as a transcriptionally and immunologically distinct entity and provide a rationale for targeted immunotherapy.