{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:24:06Z","timestamp":1787217846350,"version":"build-2736575974"},"reference-count":116,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"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>The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial\u2013myeloid neighborhoods and a macrophage\u2013fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it.<\/jats:p>","DOI":"10.3390\/cancers18162696","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:10:20Z","timestamp":1787213420000},"page":"2696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Liver Tumor Microenvironment in Hepatocellular Carcinoma: Comparisons with Intrahepatic Cholangiocarcinoma and Therapeutic Implications"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2899-4030","authenticated-orcid":false,"given":"Kizuki","family":"Yuza","sequence":"first","affiliation":[{"name":"Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA"},{"name":"Department of Gastroenterological Surgery, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Akabane","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7994-9870","authenticated-orcid":false,"given":"Timothy M.","family":"Pawlik","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","first-page":"e70090","article-title":"Global Cancer Statistics 2024: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 34 Cancers in 186 Countries","volume":"76","author":"Sung","year":"2026","journal-title":"CA Cancer J. 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