Primary central nervous system lymphoma in the molecular era: genomic drivers, liquid biopsy, and targeted therapeutic strategies.

Primary central nervous system lymphoma (PCNSL) is an uncommon and aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system, including the brain, leptomeninges, spinal cord, and eyes. Although high-dose methotrexate-based induction remains the backbone of first-line therapy, long-term disease control remains challenging, particularly in older or frail patients and in those with relapsed or refractory disease. Recent genomic and multi-omics studies have reshaped the biological understanding of PCNSL by identifying recurrent alterations in MYD88, CD79B, PIM1, PRDM1, CDKN2A/B, HLA-related genes, B2M, CIITA, and immune checkpoint loci, which converge on B-cell receptor/Toll-like receptor signaling, NF-κB activation, immune evasion, and microenvironmental adaptation. These molecular insights have accelerated minimally invasive diagnostics, including targeted mutation assays, multigene circulating tumor DNA profiling, methylation-based approaches, and cytokine analysis in cerebrospinal fluid, vitreous humor, and aqueous humor. Targeted and immune-based therapies, including Bruton tyrosine kinase inhibitors, immunomodulatory agents, immune checkpoint inhibitors, mTOR inhibitors, and CD19-directed chimeric antigen receptor T-cell therapy, have shown variable degrees of clinical activity, particularly in relapsed or refractory disease. However, most evidence remains derived from early-phase trials, single-arm studies, retrospective cohorts, or small series, and treatment selection is not yet routinely biomarker-defined. This review summarizes current advances in molecular taxonomy, pathogenesis, diagnostic work-up, liquid biopsy, prognostic stratification, and therapeutic management of PCNSL, emphasizing how molecular and longitudinal biomarker data may inform individualized treatment and future clinical trial design.