Genetic orchestration of the primary central nervous system lymphoma microenvironment

Abstract Primary central nervous system lymphoma (PCNSL) of the CNS is a distinct entity of diffuse large B-cell lymphoma (DLBCL). CNS lymphomas primarily occur in immune-privileged sites and tend to be confined to extranodal locations such as the brain, spinal cord, meninges, and/or eyes. Due to the presence of the blood-brain barrier and the inherent “immune privilege” characteristics of brain tissue, the tumor microenvironment (TME) of PCNSL exhibits unique features. Additionally, genetic factors originating from the lymphoma cells themselves significantly influence the TME. Substantial evidence has demonstrated that PCNSL exhibits highly characteristic molecular genetic alterations, with a mutational profile distinctly different from that of systemic DLBCL. These unique genetic variations collectively shape the malignant biological behavior of PCNSL, including activation of signal transduction, evasion of immune surveillance, and promotion of malignant progression. Here, we synthesize current evidence to conceptualize the genetic-TME axis as a unifying framework for PCNSL biology, wherein tumor-intrinsic genetic alterations and the specialized CNS microenvironment interact bidirectionally to shape immune evasion, tumor evolution, and therapeutic response. We review the distinctive genetic landscape of PCNSL, the cellular and molecular architecture of its TME, and the reciprocal mechanisms linking these compartments during disease progression. Integrating these dimensions may refine molecular stratification, facilitate biomarker-guided therapeutic selection, and inform more rational treatment strategies for PCNSL.