Colorectal cancer (CRC) is a highly prevalent and deadly gastrointestinal malignancy worldwide, driven by both genetic alterations and epigenetic reprogramming. The nuclear receptor-binding SET domain protein 2 (NSD2) is a type of methyltransferase that catalyzes histone H3 Lysine 36 dimethylation (H3K36me2) as its core function, and is abnormally overexpressed in various tumors. Existing evidence suggests that NSD2 mainly functions in CRC through the pro cancer chain of "epigenetic writing-chromatin remodel-ing-transcriptional program rearrangement". In addition, NSD2 can amplify key signals such as metastasis-related signals, DNA damage repair, and stress adaptation pathways by methylating non histone substrates, and drive metabolic reprogramming, thereby promoting invasion and metastasis, treatment tolerance, and changes in the tumor microenvironment. In clinical practice, NSD2 has the potential to serve as a prognostic/therapeutic biomarker and epigenetic therapy target for CRC. This article focuses on the NSD2-H3K36me2 axis, reviews epigenetic regulatory mechanisms of NSD2 in CRC, its association with metabo-lism/microenvironment/therapeutic sensitivity, and the research progress on targeted inhibition and degradation strategies. It also proposes future key directions for translational research.

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