Proteomic Landscape Uncovers Chemotherapy Resistance, Relapse Mechanisms, and Molecular Subtypes in Primary Central Nervous System Lymphoma for Precision Therapeutics

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive diffuse large B-cell lymphoma (DLBCL) subtype restricted to the CNS, with variable response to high-dose methotrexate and frequent relapse. We conducted the first comprehensive proteomic analysis of 52 PCNSL tumors to investigate mechanisms of chemoresistance, relapse, and therapeutic stratification. Chemoresistant tumors showed increased ribosomal biogenesis and reduced oxidative phosphorylation. Relapsed tumors exhibited PI3K/AKT activation and cytokine shifts, supporting survival and immune evasion, and highlighting potential targets. Biomarker analysis identified CCDC9 (chemoresistance), CD47 (relapse), and GRIA4, GAPVD1, and REPS1 (survival) as candidate predictors of clinical outcome. Unsupervised clustering defined four subtypes (C1-C4) driven by diverse pathways, including MYC, MAPK, mTOR, or glycolysis signatures. Subtypes C1-C3 may benefit from BTK inhibitors due to partial BCR, TLR, and NF-κB activation, while C4 lacks these signals. These findings support proteomics-guided precision therapy in PCNSL.