KMT2D, a key factor in driving cellular transformation and influencing therapeutic response across cancer lineages.

Histone lysine methylation, primarily mediated by the enhancer methyltransferase KMT2D (MLL4), regulates gene expression through H3K4 mono- and di-methylation. Dysregulation of KMT2D disrupts enhancer activation and contributes to tumorigenesis and cellular plasticity across multiple cancers, including lung, prostate, bladder, head and neck, and pancreatic tumors. KMT2D functions in a context-dependent manner, acting as either a tumor suppressor or oncogenic driver, and modulates key phenotypic transitions-such as epithelial-to-mesenchymal, squamous, endothelial, and neuroendocrine states-that underlie metastasis and therapeutic resistance. Beyond its tumor-intrinsic roles, KMT2D loss remodels the tumor immune microenvironment by enhancing antigen presentation and effector T-cell infiltration, thereby sensitizing tumors to immune checkpoint blockade. Understanding how KMT2D interfaces with signaling pathways such as PI3K/AKT, TGF-β, and NOTCH to regulate plasticity and immunogenicity will be critical for leveraging its biomarker and therapeutic potential. This review summarizes current insights into KMT2D's roles in cancer progression, lineage plasticity, therapy resistance, and immune regulation, highlighting its emerging relevance in precision oncology.