{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:06:44Z","timestamp":1781712404163,"version":"3.54.5"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"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":"Background<\/jats:title>Intrahepatic cholangiocarcinoma (ICC) typically exhibits poor responsiveness to immune checkpoint inhibitors (ICIs) due to its microsatellite-stable (MSS) status and low tumor mutational burden (TMB). Conventional biomarkers like PD-L1 expression show limited predictive value, creating an urgent need for novel therapeutic targets in this aggressive malignancy.<\/jats:p><\/jats:sec>Case presentation<\/jats:title>We describe a stage IV ICC patient with PD-L1 positivity and a somatic KMT2D mutation (p.R5303C) who attained sustained complete remission after pembrolizumab treatment, despite developing severe multi-organ immune-related adverse events (irAEs) including hepatitis, pneumonitis, and thrombocytopenia. Mechanistic analysis revealed that KMT2D deficiency potentially remodeled the tumor immune microenvironment through epigenetic reprogramming, characterized by enhanced CD8+ T-cell infiltration.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our findings advocate for combinatorial biomarker strategies incorporating epigenetic markers (KMT2D status) with PD-L1 expression to optimize ICI patient selection, while highlighting the need for vigilant toxicity monitoring in this subset.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1616361","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T05:35:32Z","timestamp":1755149732000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiaofang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00600-w","article-title":"Immune-checkpoint inhibitors: long-term implications of toxicity","volume":"19","author":"Johnson","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(21)00409-5","article-title":"Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, 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