{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:01Z","timestamp":1785424981297,"version":"3.56.0"},"reference-count":90,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013394","name":"National Institute of Genomic Medicine","doi-asserted-by":"publisher","award":["Grant No. 30 - PRESEPI"],"award-info":[{"award-number":["Grant No. 30 - PRESEPI"]}],"id":[{"id":"10.13039\/501100013394","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Grant No. 30 - PRESEPI"],"award-info":[{"award-number":["Grant No. 30 - PRESEPI"]}],"id":[{"id":"https:\/\/ror.org\/01qjckx08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is sustained by coordinated interactions among malignant hepatocytes, immune cells, and stromal populations that collectively drive tumor growth, immune evasion, and vascular remodeling. Using integrative single-cell transcriptomics on 93,032 cells from tumor and healthy human liver, we characterized cell-type-specific transcriptional programs underlying immunometabolic reprogramming and reconstructed the intercellular communication circuits that maintain the tumor microenvironment. Malignant hepatocytes displayed upregulation of genes encoding both glycolytic and oxidative phosphorylation (OXPHOS) metabolic enzymes, consistent with metabolic plasticity, while concurrently suppressing genes involved in antigen presentation\u2014a transcriptional pattern indicative of coordinated metabolic and immune-evasive reprogramming. Tumor-associated macrophages acquired TREM2-enriched, lipid-handling phenotypes consistent with immunosuppressive polarization, and tumor endothelial cells upregulated angiocrine and extracellular matrix programs while silencing innate immune outputs. Ligand\u2013receptor inference revealed a qualitative rewiring of intercellular communication: the antigen-presentation-centered network of the healthy liver was replaced by a tumor-driven architecture dominated by pro-angiogenic, ECM\u2013integrin, inflammatory chemokine, and lipid-associated signaling circuits, with malignant hepatocytes, TAMs, and TECs collectively assuming the dominant signaling burden. These findings establish that HCC progression is an emergent property of a stabilized multicellular network, rather than the autonomous behavior of malignant cells, and define cooperative immunometabolic modules that constitute tractable targets for combinatorial therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms27125397","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:49:01Z","timestamp":1781570941000},"page":"5397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell Transcriptomic Profiling Reveals Immunometabolic Reprogramming and Cell-Cell Communication in the Tumor Microenvironment of Human Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0780-7990","authenticated-orcid":false,"given":"Miguel \u00c1ngel","family":"D\u00edaz-Campos","sequence":"first","affiliation":[{"name":"Graduate Program in Biochemical Sciences, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"},{"name":"Computational Genomics Division, Instituto Nacional de Medicina Gen\u00f3mica, Mexico City 14610, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-1397","authenticated-orcid":false,"given":"Enrique","family":"Hern\u00e1ndez-Lemus","sequence":"additional","affiliation":[{"name":"Computational Genomics Division, Instituto Nacional de Medicina Gen\u00f3mica, Mexico City 14610, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gomez-Quiroz, L.E., and Roman, S. (2022). Influence of genetic and environmental risk factors in the development of hepatocellular carcinoma in Mexico. Ann. Hepatol., 27.","DOI":"10.1016\/j.aohep.2021.100649"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"El-Serag, H.B. (2020). Epidemiology of hepatocellular carcinoma. The Liver: Biology and Pathobiology, Wiley.","DOI":"10.1002\/9781119436812.ch59"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0300-483X(02)00253-6","article-title":"Molecular pathogenesis of human hepatocellular carcinoma","volume":"181","author":"Wang","year":"2002","journal-title":"Toxicology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1053\/j.semdp.2016.12.011","article-title":"The diagnosis and treatment of hepatocellular carcinoma","volume":"Volume 34","author":"Hartke","year":"2017","journal-title":"Proceedings of the Seminars in Diagnostic Pathology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2147\/JHC.S61146","article-title":"Hepatocellular carcinoma: A review","volume":"3","author":"Balogh","year":"2016","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/ng0802-339","article-title":"Molecular pathogenesis of human hepatocellular carcinoma","volume":"31","author":"Thorgeirsson","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sevic, I., Spinelli, F.M., Cantero, M.J., Reszegi, A., Kovalszky, I., Garc\u00eda, M.G., and Alaniz, L. (2019). The role of the tumor microenvironment in the development and progression of hepatocellular carcinoma. Hepatocellular Carcinoma, Exon Publications.","DOI":"10.15586\/hepatocellularcarcinoma.2019.ch2"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/j.gastro.2016.11.048","article-title":"Liver cancer cell of origin, molecular class, and effects on patient prognosis","volume":"152","author":"Sia","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chen, C., Wang, Z., Ding, Y., and Qin, Y. (2023). Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1133308"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xie, Z., Huang, J., Li, Y., Zhu, Q., Huang, X., Chen, J., Wei, C., Luo, S., Yang, S., and Gao, J. (2023). Single-cell RNA sequencing revealed potential targets for immunotherapy studies in hepatocellular carcinoma. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-46132-w"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ye, J., Lin, Y., Liao, Z., Gao, X., Lu, C., Lu, L., Huang, J., Huang, X., Huang, S., and Yu, H. (2024). Single cell-spatial transcriptomics and bulk multi-omics analysis of heterogeneity and ecosystems in hepatocellular carcinoma. npj Precis. Oncol., 8.","DOI":"10.1038\/s41698-024-00752-1"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Dai, H., Tao, X., Shu, Y., Liu, F., Cheng, X., Li, X., Shu, B., Luo, H., Chen, X., and Cheng, Z. (2025). Integrating single-cell RNA-Seq and bulk RNA-Seq data to explore the key role of fatty acid metabolism in hepatocellular carcinoma. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-85506-0"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/hep4.1854","article-title":"Single-cell, single-nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity","volume":"6","author":"Andrews","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Arvanitakis, K., Koletsa, T., Mitroulis, I., and Germanidis, G. (2022). Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. Cancers, 14.","DOI":"10.3390\/cancers14010226"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.jhep.2020.06.004","article-title":"Single-cell genomics and spatial transcriptomics: Discovery of novel cell states and cellular interactions in liver physiology and disease biology","volume":"73","author":"Saviano","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lu, Y., Yang, A., Quan, C., Pan, Y., Zhang, H., Li, Y., Gao, C., Lu, H., Wang, X., and Cao, P. (2022). A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat. Commun., 13.","DOI":"10.1038\/s41467-022-32283-3"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1097\/HEP.0000000000000673","article-title":"Single-cell dissection of the multicellular ecosystem and molecular features underlying microvascular invasion in HCC","volume":"79","author":"Li","year":"2024","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.cell.2020.11.041","article-title":"Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma","volume":"184","author":"Sun","year":"2021","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Devan, A.R., Nair, B., Pradeep, G.K., Alexander, R., Vinod, B.S., Nath, L.R., Calina, D., and Sharifi-Rad, J. (2024). The role of glypican-3 in hepatocellular carcinoma: Insights into diagnosis and therapeutic potential. Eur. J. Med. Res., 29.","DOI":"10.1186\/s40001-024-02073-2"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.3892\/ijo.2015.3312","article-title":"Transformation of primary human hepatocytes in hepatocellular carcinoma","volume":"48","author":"Montalbano","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1111\/febs.15587","article-title":"Metabolic heterogeneity of human hepatocellular carcinoma: Implications for personalized pharmacological treatment","volume":"288","author":"Berndt","year":"2021","journal-title":"FEBS J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wu, J., Liu, N., Chen, J., Tao, Q., Li, Q., Li, J., Chen, X., and Peng, C. (2024). The tricarboxylic acid cycle metabolites for cancer: Friend or enemy. Research, 7.","DOI":"10.34133\/research.0351"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gao, B., Lu, Y., Lai, X., Xu, X., Gou, S., Yang, Z., Gong, Y., and Yang, H. (2025). Metabolic reprogramming in hepatocellular carcinoma: Mechanisms of immune evasion and therapeutic implications. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1592837"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.7150\/jca.92185","article-title":"Single-cell RNA-seq elucidates the crosstalk between cancer stem cells and the tumor microenvironment in hepatocellular carcinoma","volume":"15","author":"Lin","year":"2024","journal-title":"J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6803","DOI":"10.21037\/tcr-2025-606","article-title":"Single-cell analysis revealed a diagnostic model of hepatocellular carcinoma based on cancer stem cell-related gene","volume":"14","author":"Ding","year":"2025","journal-title":"Transl. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/cac2.12345","article-title":"Tumor-associated macrophages in liver cancer: From mechanisms to therapy","volume":"42","author":"Cheng","year":"2022","journal-title":"Cancer Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-025-03377-9","article-title":"Tumor-associated macrophages remodel the suppressive tumor immune microenvironment and targeted therapy for immunotherapy","volume":"44","author":"Yang","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lin, Y., Xu, J., and Lan, H. (2019). Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications. J. Hematol. Oncol., 12.","DOI":"10.1186\/s13045-019-0760-3"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, J., Geng, X., Hou, J., and Wu, G. (2021). New insights into M1\/M2 macrophages: Key modulators in cancer progression. Cancer Cell Int., 21.","DOI":"10.1186\/s12935-021-02089-2"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1002\/ijc.28268","article-title":"Endothelial plasticity governs the site-specific leukocyte recruitment in hepatocellular cancer","volume":"133","author":"Salnikova","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1038\/s41556-024-01469-w","article-title":"LIANA+ provides an all-in-one framework for cell\u2013cell communication inference","volume":"26","author":"Dimitrov","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cheng, C., Chen, W., Jin, H., and Chen, X. (2023). A review of single-cell rna-seq annotation, integration, and cell\u2013cell communication. Cells, 12.","DOI":"10.3390\/cells12151970"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sung, P.S. (2021). Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma. Clin. Mol. Hepatol., 28.","DOI":"10.3350\/cmh.2021.0308"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1172\/JCI93562","article-title":"The balancing act of the liver: Tissue regeneration versus fibrosis","volume":"128","author":"Huch","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Roy, A.M., Iyer, R., and Chakraborty, S. (2023). The extracellular matrix in hepatocellular carcinoma: Mechanisms and therapeutic vulnerability. Cell Rep. Med., 4.","DOI":"10.1016\/j.xcrm.2023.101170"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Yuan, Y., Wu, D., Li, J., Huang, D., Zhao, Y., Gao, T., Zhuang, Z., Cui, Y., Zheng, D.Y., and Tang, Y. (2023). Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1217400"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Wu, X., Yu, X., Chen, C., Chen, C., Wang, Y., Su, D., and Zhu, L. (2024). Fibrinogen and tumors. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1393599"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Li, Z., Zhang, J., Mafa, T., Zhang, J., Zhu, H., Chen, L., Zong, Z., and Yang, L. (2025). Fibrinogen: A new player and target on the formation of pre-metastatic niche in tumor metastasis. Crit. Rev. Oncol., 207.","DOI":"10.1016\/j.critrevonc.2025.104625"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kim, H.S., Choi, J.Y., Jang, S.H., Kang, M., Yoon, M.G., Baek, G.O., Park, W., Han, J.E., Cho, H.J., and Jeong, J.Y. (2025). Fibrinogen alpha and beta chains as non-invasive predictors of hepatocellular carcinoma progression. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-26639-0"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Han, X., Liu, Z., Cui, M., Lin, J., Li, Y., Qin, H., Sheng, J., and Zhang, X. (2024). FGA influences invasion and metastasis of hepatocellular carcinoma through the PI3K\/AKT pathway. Aging, 16.","DOI":"10.18632\/aging.206011"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sas, Z., Cendrowicz, E., Weinh\u00e4user, I., and Rygiel, T.P. (2022). Tumor microenvironment of hepatocellular carcinoma: Challenges and opportunities for new treatment options. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073778"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/hep.32740","article-title":"The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma","volume":"77","author":"Donne","year":"2023","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2019.10.003","article-title":"Landscape and dynamics of single immune cells in hepatocellular carcinoma","volume":"179","author":"Zhang","year":"2019","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/cac2.12316","article-title":"The theory of tumor ecosystem","volume":"42","author":"Chen","year":"2022","journal-title":"Cancer Commun."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wang, Q., Liu, J., Chen, Z., Zheng, J., Wang, Y., and Dong, J. (2024). Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomed. Pharmacother., 170.","DOI":"10.1016\/j.biopha.2023.116021"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hu, N., Li, H., Tao, C., Xiao, T., and Rong, W. (2024). The role of metabolic reprogramming in the tumor immune microenvironment: Mechanisms and opportunities for immunotherapy in hepatocellular carcinoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115584"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s12276-025-01415-2","article-title":"Metabolic reprogramming in hepatocellular carcinoma: Mechanisms and therapeutic implications","volume":"57","author":"Park","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41575-021-00438-0","article-title":"Advances in immunotherapy for hepatocellular carcinoma","volume":"18","author":"Sangro","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Tang, W., Sun, G., Ji, G.W., Feng, T., Zhang, Q., Cao, H., Wu, W., Zhang, X., Liu, C., and Liu, H. (2023). Single-cell RNA-sequencing atlas reveals an FABP1-dependent immunosuppressive environment in hepatocellular carcinoma. J. Immunother. Cancer, 11.","DOI":"10.1136\/jitc-2023-007030"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Fan, G., Xie, T., Li, L., Tang, L., Han, X., and Shi, Y. (2024). Single-cell and spatial analyses revealed the co-location of cancer stem cells and SPP1+ macrophage in hypoxic region that determines the poor prognosis in hepatocellular carcinoma. npj Precis. Oncol., 8.","DOI":"10.1038\/s41698-024-00564-3"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhou, D., Luan, J., Huang, C., and Li, J. (2020). Tumor-associated macrophages in hepatocellular carcinoma: Friend or foe?. Gut Liver, 15.","DOI":"10.5009\/gnl20223"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Shen, K.Y., Zhu, Y., Xie, S.Z., and Qin, L.X. (2024). Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: Current status and prospectives. J. Hematol. Oncol., 17.","DOI":"10.1186\/s13045-024-01549-2"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41571-021-00573-2","article-title":"Immunotherapies for hepatocellular carcinoma","volume":"19","author":"Llovet","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Zhu, G.Q., Tang, Z., Huang, R., Qu, W.F., Fang, Y., Yang, R., Tao, C.Y., Gao, J., Wu, X.L., and Sun, H.X. (2023). CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor. Cell Discov., 9.","DOI":"10.1038\/s41421-023-00529-z"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Guo, H., Wang, M., Ni, C., Yang, C., Fu, C., Zhang, X., Chen, X., Wu, X., Hou, J., and Wang, L. (2025). TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 44.","DOI":"10.1186\/s13046-025-03287-w"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s43018-022-00357-2","article-title":"Molecular pathogenesis and systemic therapies for hepatocellular carcinoma","volume":"3","author":"Llovet","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.jhep.2024.12.016","article-title":"Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab+ bevacizumab in advanced hepatocellular carcinoma","volume":"82","author":"Cappuyns","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41416-022-01998-x","article-title":"Ferroptosis in hepatocellular carcinoma: Mechanisms and targeted therapy","volume":"128","author":"Ajoolabady","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.ccell.2024.01.007","article-title":"Precision treatment in advanced hepatocellular carcinoma","volume":"42","author":"Yang","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.jhep.2021.06.028","article-title":"Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma","volume":"75","author":"Ma","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zhang, S., Yuan, L., Danilova, L., Mo, G., Zhu, Q., Deshpande, A., Bell, A.T., Elisseeff, J., Popel, A.S., and Anders, R.A. (2023). Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence. Genome Med., 15.","DOI":"10.1186\/s13073-023-01218-y"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.apsb.2021.09.019","article-title":"Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma","volume":"12","author":"Du","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.cell.2021.12.018","article-title":"Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches","volume":"185","author":"Guilliams","year":"2022","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1097\/HEP.0000000000000341","article-title":"Spatial metabolomics and its application in the liver","volume":"79","author":"Santos","year":"2024","journal-title":"Hepatology"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Gan, W.L., Ren, X., Ng, V.H.E., Ng, L., Song, Y., Tano, V., Han, J., An, O., Xie, J., and Ng, B.Y. (2024). Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver. Cell Rep., 43.","DOI":"10.1016\/j.celrep.2024.114400"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.jhep.2023.12.023","article-title":"Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver","volume":"80","author":"Andrews","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_67","first-page":"1334","article-title":"Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing","volume":"19","author":"Liu","year":"2022","journal-title":"Cancer Biol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41591-020-01227-z","article-title":"Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics","volume":"27","author":"Muus","year":"2021","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: Large-scale single-cell gene expression data analysis","volume":"19","author":"Wolf","year":"2018","journal-title":"Genome Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/s41592-018-0229-2","article-title":"Deep generative modeling for single-cell transcriptomics","volume":"15","author":"Lopez","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"MacParland, S.A., Liu, J.C., Ma, X.Z., Innes, B.T., Bartczak, A.M., Gage, B.K., Manuel, J., Khuu, N., Echeverri, J., and Linares, I. (2018). Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun., 9.","DOI":"10.1038\/s41467-018-06318-7"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Payen, V.L., Lavergne, A., Sarika, N.A., Colonval, M., Karim, L., Deckers, M., Najimi, M., Coppieters, W., Charloteaux, B., and Sokal, E.M. (2021). Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep., 3.","DOI":"10.1016\/j.jhepr.2021.100278"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Meng, L., Du, M., Li, H., Kong, F., Yang, J., Dong, R., Zheng, S., Chen, G., Shen, Z., and Wang, J. (2025). Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia. Hepatol. Commun., 9.","DOI":"10.1097\/HC9.0000000000000710"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Wen, F., Tang, X., Xu, L., and Qu, H. (2022). Comparison of single-nucleus and single-cell transcriptomes in hepatocellular carcinoma tissue. Mol. Med. Rep., 26.","DOI":"10.3892\/mmr.2022.12855"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.cels.2020.05.010","article-title":"Solo: Doublet identification in single-cell RNA-seq via semi-supervised deep learning","volume":"11","author":"Bernstein","year":"2020","journal-title":"Cell Syst."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Ma, L., Wang, L., Chang, C.W., Heinrich, S., Dominguez, D., Forgues, M., Candia, J., Hernandez, M.O., Kelly, M., and Zhao, Y. (2020). Single-cell atlas of tumor clonal evolution in liver cancer. bioRxiv.","DOI":"10.1101\/2020.08.18.254748"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ma, L., Heinrich, S., Wang, L., Keggenhoff, F.L., Khatib, S., Forgues, M., Kelly, M., Hewitt, S.M., Saif, A., and Hernandez, J.M. (2022). Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer. Nat. Commun., 13.","DOI":"10.1038\/s41467-022-35291-5"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Revsine, M., Wang, L., Forgues, M., Behrens, S., Craig, A.J., Liu, M., Tran, B., Kelly, M., Budhu, A., and Monge, C. (2024). Lineage and ecology define liver tumor evolution in response to treatment. Cell Rep. Med., 5.","DOI":"10.1016\/j.xcrm.2024.101394"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Xu, C., Lopez, R., Mehlman, E., Regier, J., Jordan, M.I., and Yosef, N. (2021). Probabilistic harmonization and annotation of single-cell transcriptomics data with deep generative models. Mol. Syst. Biol., 17.","DOI":"10.15252\/msb.20209620"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Chen, Y., Lun, A.T., and Smyth, G.K. (2014). Differential expression analysis of complex RNA-seq experiments using edgeR. Statistical Analysis of Next Generation Sequencing Data, Springer.","DOI":"10.1007\/978-3-319-07212-8_3"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Jin, S., Guerrero-Juarez, C.F., Zhang, L., Chang, I., Ramos, R., Kuan, C.H., Myung, P., Plikus, M.V., and Nie, Q. (2021). Inference and analysis of cell-cell communication using CellChat. Nat. Commun., 12.","DOI":"10.1038\/s41467-021-21246-9"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1038\/s41596-020-0292-x","article-title":"CellPhoneDB: Inferring cell\u2013cell communication from combined expression of multi-subunit ligand\u2013receptor complexes","volume":"15","author":"Efremova","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1038\/s41596-024-01137-1","article-title":"CellPhoneDB v5: Inferring cell\u2013cell communication from single-cell multiomics data","volume":"20","author":"Petryszak","year":"2025","journal-title":"Nat. Protoc."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Cabello-Aguilar, S., Alame, M., Kon-Sun-Tack, F., Fau, C., Lacroix, M., and Colinge, J. (2020). SingleCellSignalR: Inference of intercellular networks from single-cell transcriptomics. Nucleic Acids Res., 48.","DOI":"10.1101\/2019.12.11.872895"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Hou, R., Denisenko, E., Ong, H.T., Ramilowski, J.A., and Forrest, A.R. (2020). Predicting cell-to-cell communication networks using NATMI. Nat. Commun., 11.","DOI":"10.1038\/s41467-020-18873-z"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41587-021-01206-w","article-title":"A Python library for probabilistic analysis of single-cell omics data","volume":"40","author":"Gayoso","year":"2022","journal-title":"Nat. Biotechnol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:24:24Z","timestamp":1781843064000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":90,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125397"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125397","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]}}}