Spatial multi-omics identify an immunosuppressive lipid-laden macrophage niche in primary CNS lymphoma

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. Statement of SignificanceThis study identifies a lipid-laden macrophage population that is uniquely noted in PCNSL and not systemic DLBCL, similar to those in Glioblastoma. These are distinct from microglia, implicating metabolic macrophage reprogramming in PCNSL tropism and immune evasion. This integrated spatial multi-omics study details the unique macrophage landscape in PCNSL with potential therapeutic implications.