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To identify immunotherapy\u2010susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approaches and Results:<\/jats:title>\n                    <jats:p>We performed RNA\u2010seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin\u2010associated protein beta 1 (CTNNB1) mutations. Thirty\u2010eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune\u2010enriched but immune\u2010exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer\u2010associated fibroblast (CAF) infiltration, high PD\u2010L1 expression, and TGF\u2010\u03b2 signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid\u2010induced lipid accumulation in HCC cells upregulated PD\u2010L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical\u2010shift MR imaging, had significantly longer PFS with combined immunotherapy using anti\u2013PD\u2010L1 and anti\u2010VEGF antibodies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune\u2010exhausted immunotherapy\u2010susceptible TIME.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32573","type":"journal-article","created":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T09:48:50Z","timestamp":1652521730000},"page":"77-91","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":143,"title":["Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma"],"prefix":"10.1097","volume":"77","author":[{"given":"Hiroki","family":"Murai","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, 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