{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T07:12:59Z","timestamp":1786432379603,"version":"build-2736575974"},"reference-count":137,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,18]],"date-time":"2022-12-18T00:00:00Z","timestamp":1671321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and\/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms.<\/jats:p>","DOI":"10.3390\/cancers14246245","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T08:41:41Z","timestamp":1671439301000},"page":"6245","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0863-7546","authenticated-orcid":false,"given":"Piera","family":"Federico","sequence":"first","affiliation":[{"name":"Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5383-4469","authenticated-orcid":false,"given":"Emilio Francesco","family":"Giunta","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, University of Study of Campania \u201cL. Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-1241","authenticated-orcid":false,"given":"Andrea","family":"Tufo","sequence":"additional","affiliation":[{"name":"Surgical Unit, Ospedale del Mare, 80147 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-1155","authenticated-orcid":false,"given":"Francesco","family":"Tovoli","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy"},{"name":"Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5489-5733","authenticated-orcid":false,"given":"Angelica","family":"Petrillo","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2638-3156","authenticated-orcid":false,"given":"Bruno","family":"Daniele","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,18]]},"reference":[{"key":"ref_1","first-page":"e1082","article-title":"Liver cancer in the world: Epidemiology, incidence, mortality and risk factors","volume":"5","author":"Mohammadian","year":"2018","journal-title":"WCRJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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