Integrated Genomic and Tumor Microenvironment Subtyping Improved Risk Stratification in Primary Central Nervous System Lymphoma

ABSTRACT Current prognostic models fail to capture the biological complexity of primary central nervous system lymphoma (PCNSL). We integrated whole‐genome sequencing and multiplex immunofluorescence in 68 treatment‐naïve patients to define four genomic subtypes (C1, C2, C3, and C4) with divergent survival (C4 worst: median overall survival [OS], 26 months). In parallel, a novel tumor microenvironment (TME) classification based on CD8 + T/M2 macrophage ratio stratified patients into High (> 1.5), Intermediate (0.8–1.5), and Low (< 0.8) groups. Unexpectedly, the Intermediate TME group showed the poorest outcomes (5‐year OS: 10%). Integration revealed a lethal subgroup (C4 + Intermediate TME; 9.8% of cohort) with a median OS of 3.0 months (hazard ratio = 7.24, p = 0.006). Prognostic nomograms incorporating these subtypes showed promising discriminative performance in internal validation (C‐index > 0.78), but external validation is needed. Together, these findings identify a high‐risk biological subset and provide a hypothesis‐generating framework for future biomarker‐driven risk stratification and therapeutic discovery in PCNSL.