{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:54:38Z","timestamp":1790034878115,"version":"4.0.1"},"reference-count":124,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u2013containing 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\u2013mesenchymal 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1799765","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:16:44Z","timestamp":1779949004000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular mechanisms of KMT2C alterations in gastrointestinal cancers: enhancer network destabilization, lineage plasticity, and clinical translation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xintao","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizi","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Decai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41571-025-01084-0","article-title":"The biology and therapeutic implications of heterogeneity in Barrett oesophagus and oesophageal adenocarcinoma","volume":"23","author":"McClurg","year":"2026","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-333029","article-title":"The road to a world-unified approach to the management of patients with gastric intestinal metaplasia: a review of current guidelines","volume":"73","author":"Dinis-Ribeiro","year":"2024","journal-title":"Gut"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00767-w","article-title":"Early stage gastric adenocarcinoma: clinical and molecular landscapes","volume":"20","author":"Hirata","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2025-336317","article-title":"Epigenetic therapies in hepatocellular carcinoma: emerging clinical tools and applications","author":"Bueloni","year":"2025","journal-title":"Gut"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00526-x","article-title":"Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy","volume":"4","author":"B\u00e4rthel","year":"2023","journal-title":"Nat Cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330483","article-title":"Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies","volume":"73","author":"Hong","year":"2024","journal-title":"Gut"},{"key":"B7","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1200\/JCO-24-02081","article-title":"Chimeric antigen receptor-T cells in colorectal cancer: pioneering new avenues in solid tumor immunotherapy","volume":"43","author":"Ouladan","year":"2025","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2024.07.046","article-title":"Environmental risk factors for gallbladder cancer: field-wide systematic review and meta-analysis","volume":"23","author":"Piovani","year":"2025","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102395","article-title":"Insights into the relevance of targeting fibroblasts to control cancer","volume":"6","author":"Boeker","year":"2025","journal-title":"Cell Rep Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s43556-025-00330-2","article-title":"Single-cell multi-omics in biliary tract cancers: decoding heterogeneity, microenvironment, and treatment strategies","volume":"6","author":"Tang","year":"2025","journal-title":"Mol BioMed"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000030","article-title":"Outcome of patients with HCC and liver dysfunction under immunotherapy: a systematic review and meta-analysis","volume":"77","author":"El Hajra","year":"2023","journal-title":"Hepatology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70783","article-title":"Tumour single-cell bioinformatics: from immune profiling to molecular dynamics","volume":"29","author":"Li","year":"2025","journal-title":"J Cell Mol Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2025.04.010","article-title":"Contributions of epigenomic and epitranscriptomic methylation to animal colouration","volume":"41","author":"Strowbridge","year":"2025","journal-title":"Trends Genet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1101\/gad.351956.124","article-title":"Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges","volume":"39","author":"Sarkar","year":"2025","journal-title":"Genes Dev"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262010146","article-title":"The role of alternative splicing in polyploids in response to abiotic stress","volume":"26","author":"Fatima","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.901435","article-title":"Epigenetic regulation in gastroenteropancreatic neuroendocrine tumors","volume":"12","author":"Crabtree","year":"2022","journal-title":"Front Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-01016-w","article-title":"Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression","volume":"29","author":"Luk","year":"2022","journal-title":"Cell Death Diff"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-24-0949","article-title":"Epigenetic regulation of cellular senescence in gastrointestinal cancer","volume":"24","author":"Ye","year":"2025","journal-title":"Mol Cancer Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116802","article-title":"Targeting non-histone methylation in gastrointestinal cancers: from biology to clinic","volume":"278","author":"Sun","year":"2024","journal-title":"Eur J Med Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adh4210","article-title":"The lncRNA MIR99AHG directs alternative splicing of SMARCA1 by PTBP1 to enable invadopodia formation in colorectal cancer cells","volume":"16","author":"Li","year":"2023","journal-title":"Sci Signal"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-22-1000","article-title":"Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis","volume":"21","author":"Choi","year":"2023","journal-title":"Mol Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100183","article-title":"SMARCA4 mutations in carcinomas of the esophagus, esophagogastric junction, and stomach","volume":"36","author":"Neil","year":"2023","journal-title":"Mod Pathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/s41420-025-02366-3","article-title":"Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies","volume":"11","author":"Yang","year":"2025","journal-title":"Cell Death Discov"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.931493","article-title":"Epigenetic regulation of inflammatory signaling and inflammation-induced cancer","volume":"10","author":"Tan","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s13238-021-00846-7","article-title":"Metabolic reprogramming and epigenetic modifications on the path to cancer","volume":"13","author":"Sun","year":"2022","journal-title":"Protein Cell"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.12.018","article-title":"Latent enhancers activated by stimulation in differentiated cells","volume":"152","author":"Ostuni","year":"2013","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.053","article-title":"Super-enhancers in the control of cell identity and disease","volume":"155","author":"Hnisz","year":"2013","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.035","article-title":"Master transcription factors and mediator establish super-enhancers at key cell identity genes","volume":"153","author":"Whyte","year":"2013","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.036","article-title":"Selective inhibition of tumor oncogenes by disruption of super-enhancers","volume":"153","author":"Lov\u00e9n","year":"2013","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1016\/j.ccell.2018.11.005","article-title":"Resistance to epigenetic-targeted therapy engenders tumor cell vulnerabilities associated with enhancer remodeling","volume":"34","author":"Iniguez","year":"2018","journal-title":"Cancer Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw3835","article-title":"Epigenetics as a mediator of plasticity in cancer","volume":"379","author":"Feinberg","year":"2023","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/j.cell.2017.07.007","article-title":"Enhancer reprogramming promotes pancreatic cancer metastasis","volume":"170","author":"Roe","year":"2017","journal-title":"Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s41422-019-0259-z","article-title":"Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer","volume":"30","author":"Teng","year":"2020","journal-title":"Cell Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"6041","DOI":"10.1038\/s41467-022-33377-8","article-title":"A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma","volume":"13","author":"Zhou","year":"2022","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-328154","article-title":"Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer","volume":"72","author":"Hamdan","year":"2023","journal-title":"Gut"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1053\/j.gastro.2020.06.050","article-title":"TP63, SOX2, and KLF5 establish a core regulatory circuitry that controls epigenetic and transcription patterns in esophageal squamous cell carcinoma cell lines","volume":"159","author":"Jiang","year":"2020","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01181-13","article-title":"The MLL3\/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers","volume":"33","author":"Hu","year":"2013","journal-title":"Mol Cell Biol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.molcel.2017.04.018","article-title":"Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation","volume":"66","author":"Dorighi","year":"2017","journal-title":"Mol Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0273-5","article-title":"KMT2C mediates the estrogen dependence of breast cancer through regulation of ER\u03b1 enhancer function","volume":"37","author":"Gala","year":"2018","journal-title":"Oncogene"},{"key":"B40","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.molcel.2017.06.028","article-title":"A UTX-MLL4-p300 transcriptional regulatory network coordinately shapes active enhancer landscapes for eliciting transcription","volume":"67","author":"Wang","year":"2017","journal-title":"Mol Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1016\/j.molcel.2024.02.030","article-title":"H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation","volume":"84","author":"Kubo","year":"2024","journal-title":"Mol Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nature12634","article-title":"Mutational landscape and significance across 12 major cancer types","volume":"502","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.cell.2018.02.060","article-title":"Comprehensive characterization of cancer driver genes and mutations","volume":"173","author":"Bailey","year":"2018","journal-title":"Cell"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/narcan\/zcac023","article-title":"KMT2C-deficient tumors have elevated APOBEC mutagenesis and genomic instability in multiple cancers","volume":"4","author":"Hu","year":"2022","journal-title":"NAR Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15716","article-title":"Association of KMT2C\/D loss-of-function variants with response to immune checkpoint blockades in colorectal cancer","volume":"114","author":"Liu","year":"2023","journal-title":"Cancer Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2005-6-8-227","article-title":"The SET-domain protein superfamily: protein lysine methyltransferases","volume":"6","author":"Dillon","year":"2005","journal-title":"Genome Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/ng.297","article-title":"Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells","volume":"41","author":"Wen","year":"2009","journal-title":"Nat Genet"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0034-6","article-title":"Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy","volume":"24","author":"Wang","year":"2018","journal-title":"Nat Med"},{"key":"B49","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.1038\/s41467-024-49391-x","article-title":"ASXLs binding to the PHD2\/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers","volume":"15","author":"Zhang","year":"2024","journal-title":"Nat Commun"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0019OC","article-title":"An obligate role for membrane-associated neutral sphingomyelinase activity in orienting chemotactic migration of human neutrophils","volume":"44","author":"Sitrin","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nature09692","article-title":"A unique chromatin signature uncovers early developmental enhancers in humans","volume":"470","author":"Rada-Iglesias","year":"2011","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx234","article-title":"MLL3\/MLL4 are required for CBP\/p300 binding on enhancers and super-enhancer formation in brown adipogenesis","volume":"45","author":"Lai","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22063178","article-title":"Regulation of nuclear mechanics and the impact on DNA damage","volume":"22","author":"Dos Santos","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2011.06.001","article-title":"Chromatin and the DNA damage response: the cancer connection","volume":"5","author":"Luijsterburg","year":"2011","journal-title":"Mol Oncol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvaa113","article-title":"The roles of nuclear myosin in the DNA damage response","volume":"169","author":"Cook","year":"2021","journal-title":"J Biochem"},{"key":"B56","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/j.1474-9726.2007.00354.x","article-title":"Delayed kinetics of DNA double-strand break processing in normal and pathological aging","volume":"7","author":"Sedelnikova","year":"2008","journal-title":"Aging Cell"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.08.027","article-title":"The multifaceted role of chromosomal instability in cancer and its microenvironment","volume":"174","author":"Bakhoum","year":"2018","journal-title":"Cell"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0688","article-title":"Recruitment of KMT2C\/MLL3 to DNA damage sites mediates DNA damage responses and regulates PARP inhibitor sensitivity in cancer","volume":"81","author":"Chang","year":"2021","journal-title":"Cancer Res"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201846821","article-title":"The lysine-specific methyltransferase KMT2C\/MLL3 regulates DNA repair components in cancer","volume":"20","author":"Rampias","year":"2019","journal-title":"EMBO Rep"},{"key":"B60","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13045-020-00874-6","article-title":"Participation of the ATR\/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer","volume":"13","author":"Gralewska","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13837","article-title":"ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A","volume":"7","author":"Williamson","year":"2016","journal-title":"Nat Commun"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3298","article-title":"Evolutionary dynamics of carcinogenesis and why targeted therapy does not work","volume":"12","author":"Gillies","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439246","article-title":"The extracellular matrix modulates the hallmarks of cancer","volume":"15","author":"Pickup","year":"2014","journal-title":"EMBO Rep"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"B66","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/nri3789","article-title":"Immune cell promotion of metastasis","volume":"15","author":"Kitamura","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0040-3","article-title":"Identification of the tumour transition states occurring during EMT","volume":"556","author":"Pastushenko","year":"2018","journal-title":"Nature"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8166","article-title":"Stability of the hybrid epithelial\/mesenchymal phenotype","volume":"7","author":"Jolly","year":"2016","journal-title":"Oncotarget"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1348","article-title":"Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer","volume":"348","author":"Rizvi","year":"2015","journal-title":"Science"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2703","article-title":"Innate and adaptive immune cells in the tumor microenvironment","volume":"14","author":"Gajewski","year":"2013","journal-title":"Nat Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80005","article-title":"Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected","volume":"125","author":"Marvel","year":"2015","journal-title":"J Clin Invest"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as regulators of tumour immunity and immunotherapy","volume":"19","author":"DeNardo","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat Med"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-023-04734-7","article-title":"Loss of Kmt2c in vivo leads to EMT, mitochondrial dysfunction and improved response to lapatinib in breast cancer","volume":"80","author":"Simigdala","year":"2023","journal-title":"Cell Mol Life Sci"},{"key":"B75","doi-asserted-by":"publisher","first-page":"444","DOI":"10.3892\/ol.2024.14577","article-title":"Pan-cancer analysis on the role of KMT2C expression in tumor progression and immunotherapy","volume":"28","author":"Cao","year":"2024","journal-title":"Oncol Lett"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3949","article-title":"The selection and function of cell type-specific enhancers","volume":"16","author":"Heinz","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B77","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1002\/cac2.12138","article-title":"EMT-associated microRNAs and their roles in cancer stemness and drug resistance","volume":"41","author":"Pan","year":"2021","journal-title":"Cancer Commun Lond"},{"key":"B78","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/ncb2897","article-title":"Causes and consequences of replication stress","volume":"16","author":"Zeman","year":"2014","journal-title":"Nat Cell Biol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.018","article-title":"Clonal heterogeneity and tumor evolution: past, present, and the future","volume":"168","author":"McGranahan","year":"2017","journal-title":"Cell"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.002","article-title":"Endogenous DNA damage as a source of genomic instability in cancer","volume":"168","author":"Tubbs","year":"2017","journal-title":"Cell"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.10.040","article-title":"Targeting the DNA damage response in cancer","volume":"60","author":"O'Connor","year":"2015","journal-title":"Mol Cell"},{"key":"B82","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1093\/annonc\/mdy495","article-title":"Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic","volume":"30","author":"Chan","year":"2019","journal-title":"Ann Oncol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3947","article-title":"Loss of BAP1 function leads to EZH2-dependent transformation","volume":"21","author":"LaFave","year":"2015","journal-title":"Nat Med"},{"key":"B84","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.cell.2017.05.046","article-title":"Comprehensive and integrative genomic characterization of hepatocellular carcinoma","volume":"169","year":"2017","journal-title":"Cell"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1101\/gr.154492.113","article-title":"Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma","volume":"23","author":"Kan","year":"2013","journal-title":"Genome Res"},{"key":"B86","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s12072-022-10455-z","article-title":"Integrated genomic analyses of hepatocellular carcinoma","volume":"17","author":"Chang","year":"2023","journal-title":"Hepatol Int"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.80854","article-title":"MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer","volume":"12","author":"Zhu","year":"2023","journal-title":"Elife"},{"key":"B88","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1101\/gad.244368.114","article-title":"CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma","volume":"28","author":"Huang","year":"2014","journal-title":"Genes Dev"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30544","article-title":"Aberrant super-enhancer landscape in human hepatocellular carcinoma","volume":"69","author":"Tsang","year":"2019","journal-title":"Hepatology"},{"key":"B91","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1053\/j.gastro.2015.05.061","article-title":"Genetic landscape and biomarkers of hepatocellular carcinoma","volume":"149","author":"Zucman-Rossi","year":"2015","journal-title":"Gastroenterology"},{"key":"B92","doi-asserted-by":"publisher","first-page":"78","DOI":"10.18632\/genesandcancer.171","article-title":"Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential","volume":"9","author":"Cannon","year":"2018","journal-title":"Genes Cancer"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-031621-024600","article-title":"Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance","volume":"18","author":"Sherman","year":"2023","journal-title":"Annu Rev Pathol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.66","article-title":"Pancreatic cancer biology and genetics from an evolutionary perspective","volume":"16","author":"Makohon-Moore","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.605619","article-title":"Tumor-derived myeloid cell chemoattractants and T cell exclusion in pancreatic cancer","volume":"11","author":"Vonderheide","year":"2020","journal-title":"Front Immunol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1177\/20552076221133699","article-title":"Mutations in lysine methyltransferase 2C and PEG3 are associated with tumor mutation burden, prognosis, and antitumor immunity in pancreatic adenocarcinoma patients","volume":"8","author":"Huang","year":"2022","journal-title":"Digit Health"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-0481","article-title":"Reduced expression of histone methyltransferases KMT2C and KMT2D correlates with improved outcome in pancreatic ductal adenocarcinoma","volume":"76","author":"Dawkins","year":"2016","journal-title":"Cancer Res"},{"key":"B98","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41392-021-00659-4","article-title":"The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduc Tgt Ther"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8060903","article-title":"Alteration of epigenetic modifiers in pancreatic cancer and its clinical implication","volume":"8","author":"Hung","year":"2019","journal-title":"J Clin Med"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-3581","article-title":"Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma","volume":"28","author":"Philip","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.5009\/gnl18355","article-title":"Comprehensive cancer panel sequencing defines genetic diversity and changes in the mutational characteristics of pancreatic cancer patients receiving neoadjuvant treatment","volume":"13","author":"Yoon","year":"2019","journal-title":"Gut Liver"},{"key":"B102","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/s13046-020-01732-6","article-title":"KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities","volume":"39","author":"Luchini","year":"2020","journal-title":"J Exp Clin Cancer Res"},{"key":"B103","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1186\/s12885-019-5391-0","article-title":"Molecular pathogenesis of cholangiocarcinoma","volume":"19","author":"Labib","year":"2019","journal-title":"BMC Cancer"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2022.101514","article-title":"Targeting tumor microenvironment for cholangiocarcinoma: opportunities for precision medicine","volume":"25","author":"Carloni","year":"2022","journal-title":"Transl Oncol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01439","article-title":"Genomic features and clinical characteristics of adolescents and young adults with cholangiocarcinoma","volume":"9","author":"Feng","year":"2020","journal-title":"Front Oncol"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103375","article-title":"Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target","volume":"67","author":"Zhou","year":"2021","journal-title":"EBioMedicine"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.10.043","article-title":"Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma","volume":"82","author":"Yoo","year":"2025","journal-title":"J Hepatol"},{"key":"B108","doi-asserted-by":"publisher","first-page":"13261","DOI":"10.1038\/s41598-019-49860-0","article-title":"Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information","volume":"9","author":"Ettrich","year":"2019","journal-title":"Sci Rep"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100762","article-title":"Spatial immunophenotypes predict clinical outcome in intrahepatic cholangiocarcinoma","volume":"5","author":"Zhu","year":"2023","journal-title":"JHEP Rep"},{"key":"B110","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/hep.31410","article-title":"The tumor microenvironment in cholangiocarcinoma progression","author":"Fabris","year":"2021","journal-title":"Hepatology"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252","article-title":"Comprehensive molecular characterization of human colon and rectal cancer","volume":"487","year":"2012","journal-title":"Nature"},{"key":"B112","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13148-020-00863-z","article-title":"Restoration of KMT2C\/MLL3 in human colorectal cancer cells reinforces genome-wide H3K4me1 profiles and influences cell growth and gene expression","volume":"12","author":"Larsson","year":"2020","journal-title":"Clin Epigenet"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.4238\/2014","article-title":"Association of MLL3 expression with prognosis in gastric cancer","volume":"13","author":"Li","year":"2014","journal-title":"Genet Mol Res"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-023-02338-3","article-title":"Genomic and evolutionary characteristics of metastatic gastric cancer by routes","volume":"129","author":"Lee","year":"2023","journal-title":"Br J Cancer"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.335","article-title":"The epigenetic modifier lysine methyltransferase 2C is frequently mutated in gastric remnant carcinoma","volume":"9","author":"Sun","year":"2023","journal-title":"J Pathol Clin Res"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0312-8","article-title":"Tumor mutational load predicts survival after immunotherapy across multiple cancer types","volume":"51","author":"Samstein","year":"2019","journal-title":"Nat Genet"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-25-0625","article-title":"Distinct spatially resolved tumor microenvironment trajectories define benefit from ramucirumab plus pembrolizumab in refractory PD-L1+ gastric cancer","volume":"14","author":"Lim","year":"2025","journal-title":"Cancer Immunol Res"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-025-01621-x","article-title":"Circulating tumor DNA predicts clinical benefits of immune checkpoint blockade in HER2-negative patients with advanced gastric cancer","volume":"28","author":"He","year":"2025","journal-title":"Gastric Cancer"},{"key":"B119","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nature25167","article-title":"Senescence-associated reprogramming promotes cancer stemness","volume":"553","author":"Milanovic","year":"2018","journal-title":"Nature"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1444923","article-title":"The modification role and tumor association with a methyltransferase: KMT2C","volume":"15","author":"Jiao","year":"2024","journal-title":"Front Immunol"},{"key":"B121","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41556-018-0249-2","article-title":"The dynamic nature of senescence in cancer","volume":"21","author":"Lee","year":"2019","journal-title":"Nat Cell Biol"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i22.3978","article-title":"Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update","volume":"23","author":"Sharma","year":"2017","journal-title":"World J Gastroenterol"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-1954","article-title":"Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention","volume":"28","author":"Giraldo","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-024-02745-0","article-title":"ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors","volume":"131","author":"Smith","year":"2024","journal-title":"Br J Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1799765\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:16:47Z","timestamp":1779949007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1799765\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":124,"alternative-id":["10.3389\/fimmu.2026.1799765"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1799765","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"article-number":"1799765"}}