{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T18:08:47Z","timestamp":1779300527188,"version":"3.51.4"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072627"],"award-info":[{"award-number":["82072627"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373159"],"award-info":[{"award-number":["82373159"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023B1111020008"],"award-info":[{"award-number":["2023B1111020008"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>\n                    Crosstalk between hepatocellular carcinoma (HCC) and the tumor microenvironment (TME) is pivotal for the initiation and management of HCC. The infiltration and function of natural killer (NK) cells in the TME are frequently hindered. However, it is unclear whether a crucial regulatory factor originating from HCC cells directly modulates NK cell activity to evade immune surveillance. In this study, we found that mannose-binding lectin 2 (MBL2) expression was markedly decreased in HCC and positively correlated with HCC prognosis. MBL2 inhibited the proliferation and migration of HCC cells intracellularly. Human and murine co-culture systems of HCC and NK cells were established to demonstrate that secreted MBL2 recruited and activated NK cells in the TME, particularly upregulating the infiltration of NKp46\n                    <jats:sup>+<\/jats:sup>\n                    NK cells. Furthermore, secreted MBL2 promoted the production of IL-13 and IL-25 by NK cells, resulting in a decrease in exhausted cytotoxic T lymphocytes. Mechanistically, MBL2 interacts with the integrin \u03b21 receptor, activating the FAK\/AKT pathway and increasing PD-L1 expression on NK cells. Our discovery identifies MBL2 as an NK cell\u2013activating cytokine, initiating the integrin \u03b21\/FAK\/AKT pathway in NK cells and reshaping an immune-activated microenvironment of HCC. Strategies to up-regulate MBL2 may enhance the anti-PD-L1 immunotherapy efficacy and serve as a potential therapeutic approach for HCC.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003793","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:31:30Z","timestamp":1779298290000},"page":"e3003793","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mannose-binding lectin 2 secreted by hepatocellular carcinoma cells recruits and activates natural killer cells to reshape an immune-activated microenvironment"],"prefix":"10.1371","volume":"24","author":[{"given":"Hangyu","family":"Liao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luhao","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juncheng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyuan","family":"Pei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zesheng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1429-0884","authenticated-orcid":true,"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"pbio.3003793.ref001","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"H Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"7938","key":"pbio.3003793.ref002","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41586-022-05400-x","article-title":"Liver tumour immune microenvironment subtypes and neutrophil heterogeneity","volume":"612","author":"R Xue","year":"2022","journal-title":"Nature"},{"issue":"19","key":"pbio.3003793.ref003","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2023.07.034","article-title":"A pan-cancer single-cell panorama of human natural killer cells","volume":"186","author":"F Tang","year":"2023","journal-title":"Cell"},{"issue":"6","key":"pbio.3003793.ref004","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2020.02.029","article-title":"SnapShot: natural killer cells","volume":"180","author":"A Crinier","year":"2020","journal-title":"Cell"},{"key":"pbio.3003793.ref005","doi-asserted-by":"crossref","first-page":"1284669","DOI":"10.3389\/fimmu.2023.1284669","article-title":"Characterizing hepatocellular carcinoma stem markers and their corresponding susceptibility to NK-cell based immunotherapy","volume":"14","author":"J Chiang","year":"2023","journal-title":"Front Immunol"},{"issue":"2","key":"pbio.3003793.ref006","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ccell.2017.06.009","article-title":"Control of metastasis by NK cells","volume":"32","author":"A L\u00f3pez-Soto","year":"2017","journal-title":"Cancer Cell"},{"issue":"7","key":"pbio.3003793.ref007","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.4049\/jimmunol.2100874","article-title":"Combinatorial expression of NK cell receptors governs cell subset reactivity and effector functions but not tumor specificity","volume":"208","author":"Y Rocca","year":"2022","journal-title":"J Immunol"},{"issue":"1","key":"pbio.3003793.ref008","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1038\/s41467-021-22755-3","article-title":"IFN-\u03b3-dependent NK cell activation is essential to metastasis suppression by engineered Salmonella","volume":"12","author":"Q Lin","year":"2021","journal-title":"Nat Commun"},{"issue":"1","key":"pbio.3003793.ref009","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12943-023-01737-7","article-title":"NK cells are never alone: crosstalk and communication in tumour microenvironments","volume":"22","author":"Y Zhou","year":"2023","journal-title":"Mol Cancer"},{"issue":"4","key":"pbio.3003793.ref010","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.jhep.2023.01.011","article-title":"Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy","volume":"78","author":"Y Liu","year":"2023","journal-title":"J Hepatol"},{"issue":"1","key":"pbio.3003793.ref011","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1158\/2159-8290.CD-20-0796","article-title":"Decidual-like NK cell polarization: from cancer killing to cancer nurturing","volume":"11","author":"A Albini","year":"2021","journal-title":"Cancer Discov"},{"issue":"7817","key":"pbio.3003793.ref012","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41586-020-2422-6","article-title":"IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy","volume":"583","author":"T Zhou","year":"2020","journal-title":"Nature"},{"issue":"3","key":"pbio.3003793.ref013","doi-asserted-by":"crossref","first-page":"112147","DOI":"10.1016\/j.celrep.2023.112147","article-title":"IL-18BP mediates the balance between protective and pathological immune responses to Toxoplasma gondii","volume":"42","author":"JT Clark","year":"2023","journal-title":"Cell Rep"},{"key":"pbio.3003793.ref014","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s10875-010-9382-9","article-title":"TL1A Selectively enhances IL-12\/IL-18-induced NK cell cytotoxicity against NK-resistant tumor targets","volume":"30","author":"SC Heidemann","year":"2010","journal-title":"J Clin Immunol"},{"issue":"1","key":"pbio.3003793.ref015","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/hep.30347","article-title":"Human CD96 correlates to natural killer cell exhaustion and predicts the prognosis of human hepatocellular carcinoma","volume":"70","author":"H Sun","year":"2019","journal-title":"Hepatology"},{"issue":"3","key":"pbio.3003793.ref016","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/mi.2015.100","article-title":"Role of mannose-binding lectin in intestinal homeostasis and fungal elimination","volume":"9","author":"L Choteau","year":"2016","journal-title":"Mucosal Immunol"},{"issue":"1","key":"pbio.3003793.ref017","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1515\/med-2021-0239","article-title":"The ambiguous role of mannose-binding lectin (MBL) in human immunity","volume":"16","author":"N Kalia","year":"2021","journal-title":"Open Med (Wars)"},{"issue":"2","key":"pbio.3003793.ref018","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41590-021-01114-w","article-title":"Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules","volume":"23","author":"M Stravalaci","year":"2022","journal-title":"Nat Immunol"},{"issue":"4","key":"pbio.3003793.ref019","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/hep.510290417","article-title":"Mannose binding lectin gene mutations are associated with progression of liver disease in chronic hepatitis B infection","volume":"29","author":"MF Yuen","year":"1999","journal-title":"Hepatology"},{"issue":"7","key":"pbio.3003793.ref020","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1111\/j.1478-3231.2011.02522.x","article-title":"Association of mannose-binding lectin-2 gene polymorphism with the development of hepatitis C-induced hepatocellular carcinoma","volume":"31","author":"D Eurich","year":"2011","journal-title":"Liver Int"},{"issue":"5","key":"pbio.3003793.ref021","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2188\/jea.JE20140194","article-title":"Impact of mannose-binding lectin 2 polymorphism on the risk of hepatocellular carcinoma: a case-control study in Chinese Han population","volume":"25","author":"Y Lin","year":"2015","journal-title":"J Epidemiol"},{"key":"pbio.3003793.ref022","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"T Li","year":"2020","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pbio.3003793.ref023","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41571-021-00573-2","article-title":"Immunotherapies for hepatocellular carcinoma","volume":"19","author":"JM Llovet","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"pbio.3003793.ref024","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.cmet.2023.04.017","article-title":"Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment","volume":"35","author":"J Cheng","year":"2023","journal-title":"Cell Metabolism"},{"issue":"1","key":"pbio.3003793.ref025","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.canlet.2015.07.039","article-title":"Tumor microenvironment: sanctuary of the devil","volume":"368","author":"L Hui","year":"2015","journal-title":"Cancer Lett"},{"issue":"2","key":"pbio.3003793.ref026","article-title":"Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK\/COX-2\/PGE2 pathway","volume":"8","author":"J Li","year":"2018","journal-title":"Oncoimmunology"},{"key":"pbio.3003793.ref027","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S0076-6879(03)01041-3","article-title":"Antitumor activity of mannan-binding protein.","author":"T Nakagawa","year":"2003","journal-title":"Methods in enzymology. Elsevier"},{"issue":"1","key":"pbio.3003793.ref028","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.imlet.2006.10.006","article-title":"Mannan binding lectin and viral hepatitis","volume":"108","author":"KS Brown","year":"2007","journal-title":"Immunol Lett"},{"issue":"1","key":"pbio.3003793.ref029","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.molimm.2012.09.005","article-title":"Mannan-binding lectin in malignancy","volume":"55","author":"AS Swierzko","year":"2013","journal-title":"Mol Immunol"},{"issue":"2","key":"pbio.3003793.ref030","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1073\/pnas.96.2.371","article-title":"Antitumor activity of mannan-binding protein in vivo as revealed by a virus expression system: mannan-binding proteindependent cell-mediated cytotoxicity","volume":"96","author":"Y Ma","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pbio.3003793.ref031","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.clinre.2015.12.015","article-title":"Genetic variants of mannose-binding lectin 2 gene influence progression and prognosis of patients with hepatitis B virus infection in China","volume":"40","author":"X Gu","year":"2016","journal-title":"Clin Res Hepatol Gastroenterol"},{"issue":"3","key":"pbio.3003793.ref032","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a021402","article-title":"Hepatitis B Virus X and regulation of viral gene expression","volume":"6","author":"BL Slagle","year":"2016","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"3","key":"pbio.3003793.ref033","article-title":"Hepatitis B virus X protein recruits methyltransferases to affect cotranscriptional N6-methyladenosine modification of viral\/host RNAs","volume":"118","author":"G-W Kim","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pbio.3003793.ref034","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1053\/j.gastro.2020.01.028","article-title":"High serum levels of cholesterol increase antitumor functions of nature killer cells and reduce growth of liver tumors in mice","volume":"158","author":"W-H Qin","year":"2020","journal-title":"Gastroenterology"},{"issue":"3","key":"pbio.3003793.ref035","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1084\/jem.20111908","article-title":"Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis","volume":"209","author":"BN Jaeger","year":"2012","journal-title":"J Exp Med"},{"issue":"3","key":"pbio.3003793.ref036","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41423-019-0225-1","article-title":"Specific contribution of mannose-binding lectin murine isoforms to brain ischemia\/reperfusion injury","volume":"17","author":"L Neglia","year":"2020","journal-title":"Cell Mol Immunol"},{"issue":"4","key":"pbio.3003793.ref037","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/cmi.2016.26","article-title":"NK cell education via nonclassical MHC and non-MHC ligands","volume":"14","author":"Y He","year":"2017","journal-title":"Cell Mol Immunol"},{"issue":"1","key":"pbio.3003793.ref038","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/s41467-024-45083-8","article-title":"MHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides","volume":"15","author":"Y-T Chang","year":"2024","journal-title":"Nat Commun"},{"key":"pbio.3003793.ref039","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.4049\/jimmunol.0804337","article-title":"Myosin IIA associates with NK cell lytic granules to enable their interaction with F-Actin and function at the immunological synapse","volume":"182","author":"KB Sanborn","year":"2009","journal-title":"J Immunol"},{"issue":"9","key":"pbio.3003793.ref040","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.4049\/jimmunol.1101307","article-title":"DHX9 pairs with IPS-1 to sense double-stranded RNA in myeloid dendritic cells","volume":"187","author":"Z Zhang","year":"2011","journal-title":"J Immunol"},{"issue":"1","key":"pbio.3003793.ref041","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1038\/s41467-020-17556-z","article-title":"Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans","volume":"11","author":"LL Baggio","year":"2020","journal-title":"Nat Commun"},{"issue":"8","key":"pbio.3003793.ref042","doi-asserted-by":"crossref","first-page":"10668","DOI":"10.1096\/fj.202000043R","article-title":"THBS4 promotes HCC progression by regulating ITGB1 via FAK\/PI3K\/AKT pathway","volume":"34","author":"D Guo","year":"2020","journal-title":"FASEB J"},{"issue":"1","key":"pbio.3003793.ref043","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1136\/gutjnl-2015-309322","article-title":"hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation","volume":"66","author":"C Hu","year":"2017","journal-title":"Gut"},{"issue":"5","key":"pbio.3003793.ref044","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1158\/0008-5472.CAN-19-2332","article-title":"Tim-3 hampers tumor surveillance of liver-resident and conventional NK cells by disrupting PI3K signaling","volume":"80","author":"S Tan","year":"2020","journal-title":"Cancer Res"},{"issue":"1","key":"pbio.3003793.ref045","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1158\/2326-6066.CIR-24-0124","article-title":"CD49a targeting enhances NK cell function and antitumor immunity","volume":"13","author":"Y Zhang","year":"2025","journal-title":"Cancer Immunol Res"},{"issue":"1","key":"pbio.3003793.ref046","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1158\/2326-6066.CIR-24-0124","article-title":"CD49a targeting enhances NK cell function and antitumor immunity","volume":"13","author":"Y Zhang","year":"2025","journal-title":"Cancer Immunol Res"},{"issue":"3","key":"pbio.3003793.ref047","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1136\/gutjnl-2023-330024","article-title":"Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy","volume":"73","author":"BL Green","year":"2024","journal-title":"Gut"},{"issue":"687","key":"pbio.3003793.ref048","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.aba0717","article-title":"The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse","volume":"14","author":"S Kataoka","year":"2021","journal-title":"Sci Signal"},{"issue":"10","key":"pbio.3003793.ref049","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1158\/2159-8290.CD-18-1259","article-title":"The Mechanism of Anti-PD-L1 antibody efficacy against PD-L1-negative tumors identifies NK Cells expressing PD-L1 as a cytolytic effector","volume":"9","author":"W Dong","year":"2019","journal-title":"Cancer Discov"},{"issue":"3","key":"pbio.3003793.ref050","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.apsb.2021.08.020","article-title":"Emerging role of natural products in cancer immunotherapy","volume":"12","author":"S Dong","year":"2022","journal-title":"Acta Pharm Sin B"},{"issue":"2","key":"pbio.3003793.ref051","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s44321-023-00018-6","article-title":"Interferon-epsilon is a novel regulator of NK cell responses in the uterus","volume":"16","author":"JR Mayall","year":"2024","journal-title":"EMBO Mol Med"},{"issue":"2","key":"pbio.3003793.ref052","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1002\/JLB.3MA1220-815RRR","article-title":"IFN\u03b3-mediated repression of system xc- drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells","volume":"110","author":"R Kong","year":"2021","journal-title":"J Leukoc Biol"},{"issue":"9","key":"pbio.3003793.ref053","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1038\/bjc.2015.101","article-title":"IFN-\u03b3 from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer","volume":"112","author":"K Abiko","year":"2015","journal-title":"Br J Cancer"},{"issue":"6","key":"pbio.3003793.ref054","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.celrep.2017.04.031","article-title":"Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression","volume":"19","author":"A Garcia-Diaz","year":"2017","journal-title":"Cell Rep"},{"key":"pbio.3003793.ref055","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1182\/blood-2023-191070","article-title":"The NK cell receptor NKp46 acts as an essential regulator of ILC1 proliferation, effector function and anti-aml activity","volume":"142","author":"R Ma","year":"2023","journal-title":"Blood"},{"key":"pbio.3003793.ref056","article-title":"The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells","author":"Santara Sen","year":"2023","journal-title":"Nature"},{"issue":"7","key":"pbio.3003793.ref057","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2019.04.041","article-title":"Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity","volume":"177","author":"L Gauthier","year":"2019","journal-title":"Cell"},{"issue":"4","key":"pbio.3003793.ref058","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41575-022-00704-9","article-title":"Evolving therapeutic landscape of advanced hepatocellular carcinoma","volume":"20","author":"C Yang","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"8","key":"pbio.3003793.ref059","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1038\/s41591-022-01868-2","article-title":"Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma","volume":"28","author":"AX Zhu","year":"2022","journal-title":"Nat Med"},{"issue":"11","key":"pbio.3003793.ref060","doi-asserted-by":"crossref","DOI":"10.1172\/JCI181243","article-title":"Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs","volume":"135","author":"Q Liao","year":"2025","journal-title":"J Clin Invest"}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003793","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:31:41Z","timestamp":1779298301000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003793"}},"subtitle":[],"editor":[{"given":"Elena","family":"Rainero","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":60,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3003793","relation":{},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}