Narrative review on KMT2C alterations in gastrointestinal cancers and therapeutic implicationsGenetic changes in gut cancers may open new treatment doors for patients

KMT2C (lysine methyltransferase 2C), also known as mixed-lineage leukemia 3 (MLL3), is a member of the KMT2 family of histone methyltransferases that catalyzes histone H3 lysine 4 monomethylation (H3K4me1), a hallmark of active enhancer elements. Operating within COMPASS-like complexes (Complex of Proteins Associated with Set1) and in association with the ASCOM coactivator complex (ASC-2–containing complex), KMT2C plays a central role in maintaining enhancer and super-enhancer integrity, thereby sustaining lineage-specific transcriptional programs. Across gastrointestinal malignancies, KMT2C is recurrently altered, predominantly through truncating loss-of-function variants, splice-disrupting events, and structural alterations that impair protein function. Importantly, the biological impact of KMT2C alteration is highly context dependent, shaped by mutation class, co-occurring genomic lesions, and tissue-specific transcriptional circuitry. Rather than inducing linear dysregulation of individual signaling pathways, KMT2C deficiency preferentially destabilizes enhancer and super-enhancer networks, leading to large-scale transcriptional rewiring. Disruption of enhancer modules that enforce cellular identity and homeostasis is frequently accompanied by activation of stress-adaptive and metabolic programs. Concurrently, defects in homologous recombination and replication-stress responses promote genomic instability, while attenuation of cell-cycle checkpoints and senescence barriers facilitates epithelial–mesenchymal transition, stem-like plasticity, and invasive or metastatic behavior. Beyond tumor-intrinsic effects, KMT2C dysfunction can reshape the tumor immune microenvironment through altered antigenic burden, inflammatory signaling, senescence-associated secretory programs, and dynamic stromal interactions, ultimately giving rise to heterogeneous therapeutic vulnerabilities. Clinically, KMT2C alteration has been linked to tumor mutational burden (TMB), microsatellite instability (MSI), immune infiltration patterns, and outcomes following immune checkpoint blockade (ICB). In parallel, KMT2C-associated DNA repair deficiencies provide a mechanistic basis for synthetic-lethal strategies involving poly(ADP-ribose) polymerase (PARP) inhibitors and inhibitors of ataxia telangiectasia and Rad3-related protein (ATR) or checkpoint kinase 1 (CHK1), including rational combinations with epigenetic therapies. In this review, we integrate evidence from hepatocellular carcinoma, pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, gastric cancer, esophageal cancer, and gallbladder cancer within a unified framework that links KMT2C domain architecture to enhancer-network destabilization, phenotypic state transitions, and clinical manifestations. We further propose a functional evaluation paradigm that reframes discrete KMT2C variants as graded states of epigenetic deficiency, coupled with a closed-loop validation strategy integrating tissue-based profiling, liquid biopsy monitoring, and spatial multi-omics analyses.