{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:55:51Z","timestamp":1790207751802,"version":"4.1.0"},"reference-count":143,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is a highly lethal, heterogeneous malignancy arising from the biliary tract. Although the prevalence of CCA is relatively low, its incidence has increased in the last few decades, and the overall prognosis is poor. Surgical resection remains the most efficacious treatment modality for CCA. However, due to its aggressive nature and often asymptomatic presentation, most patients are first diagnosed with advanced disease, precluding them from curative intervention. Moreover, due to its heterogeneity at the molecular, genomic, and epigenetic levels, drug treatment of CCA remains challenging. In this review, we discuss the current standard drug treatment approaches, recent breakthroughs, and promising new therapeutics for CCA. We summarize key clinical data for the standard first-line chemotherapy regimen and its efficacy and resistance mechanisms, along with more recent studies supporting or proposing second-line treatments. We highlight landmark clinical trials, including ABC-02, which established gemcitabine-cisplatin (GC) as the first-line regimen against biliary cancers. Additionally, we discuss recent findings on the susceptibility of CCA against targeted therapies and other immunologic molecules, including results from the KEYNOTE-966 and TOPAZ-1 clinical trials. Finally, we critically analyze new therapeutics in the preclinical and clinical space, such as CAR-T cells and oncolytic viruses that may be effective against CCA.<\/jats:p>","DOI":"10.3390\/ph19040554","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T08:09:18Z","timestamp":1774944558000},"page":"554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Current Status of Drug Treatment of Cholangiocarcinoma\u2014Updated Progress and Critical Limitations"],"prefix":"10.3390","volume":"19","author":[{"given":"Jennifer","family":"Cillis","sequence":"first","affiliation":[{"name":"Department of Surgery, City of Hope, Duarte, CA 91010, USA"},{"name":"Department of Surgery, Rutgers Robert Wood Johnson Medical Center, New Brunswick, NJ 08901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Surgery, City of Hope, Duarte, CA 91010, USA"},{"name":"Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriya","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Department of Surgery, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuman","family":"Fong","sequence":"additional","affiliation":[{"name":"Department of Surgery, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9543-5458","authenticated-orcid":false,"given":"Shyambabu","family":"Chaurasiya","sequence":"additional","affiliation":[{"name":"Department of Surgery, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. 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