NSD2 is a histone methyltransferase that primarily catalyzes dimethylation of histone H3 at lysine 36 (H3K36me2) 1. Its role in transcriptional regulation remains complex, with evidence suggesting both tumor-promoting and context-dependent tumor-suppressive functions. In lung adenocarcinoma, NSD2's H3K36me2 activity cooperates with oncogenic KRAS signaling to drive pathogenesis, and NSD2 loss attenuates tumor progression 2. Similarly, NSD2 sustains neuroendocrine differentiation and castration-resistance in prostate cancer through H3K36me2-mediated enhancer regulation, with NSD2 targeting reversing lineage plasticity and restoring AR inhibitor sensitivity 34. In acute lymphoblastic leukemia, the hyperactive NSD2 variant p.E1099K promotes tumorigenesis, making it a therapeutic target 5. Conversely, in pancreatic cancer, NSD2 acts as a tumor suppressor by restraining NF-κB signaling through H3K36me2-mediated IκBα expression and direct p65 interaction 6. NSD2 translocations associate with multiple myeloma and mantle cell lymphoma as high-risk prognostic markers 789. These divergent roles suggest NSD2 functions context-dependently: promoting oncogenic transcriptional programs in epithelial tumors while suppressing inflammation-driven tumorigenesis in pancreatic tissue. NSD2 emerges as a promising therapeutic target through both enzymatic inhibition and targeted degradation strategies.