Spatial multi-omics identify an immunosuppressive lipid-laden macrophage niche in primary CNS lymphoma
Journal:
bioRxiv
Published Date:
Feb 20, 2026
Abstract
Primary central nervous system lymphoma (PCNSL) is a subtype of diffuse large B-cell lymphoma (DLBCL) with confined CNS growth. We evaluated tumor microenvironment (TME) features associated with its unique tropism. Comparative spatial transcriptomic profiling of PCNSL samples (n=17) revealed increased macrophage infiltration compared to systemic DLBCL (n=76). These macrophages showed enrichment of immunosuppressive (SPP1) and cholesterol metabolism signatures. These findings were validated across three independent PCNSL scRNA-seq cohorts (n=8,7,13), with further characterization as lipid-laden macrophages (LLMs)- like those noted in glioblastoma. These LLMs are transcriptionally distinct from microglia, derive from infiltrating monocytes, show activation of lipid metabolism, and have unique interactions with T-cells. Hyperplex spatial proteomics confirms GPNMB LLMs and identifies LLM-T cell distance as a correlate of treatment response. Together, our findings define a distinct feature of the TME in PCNSL and identify lipid-laden macrophages as a candidate population for immune modulation and therapeutic targeting
