{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T07:02:44Z","timestamp":1779692564196,"version":"3.53.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, necessitating identification of novel biomarkers for precision therapy. Herein, we aimed to investigate the role of efferocytosis-related genes (ERGs) in LUAD progression, focusing on ADAM9 as a potential prognostic and therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      TCGA-LUAD datasets including 517 tumor and 59 normal tissues were applied to perform consensus clustering, LASSO regression, and immune infiltration algorithms. A prognostic model was constructed and validated via survival analysis and nomogram. Single-cell sequencing was performed to analyze the distribution of ADAM9 in tumor microenvironment. Additionally,\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments were carried out to analyze the biological function of ADAM9 in LUAD progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Eleven ERG signatures, including ADAM9, stratified patients into high- and low-risk groups with significant survival differences. A nomogram integrating ADAM9 and clinical features demonstrated robust predictive accuracy. High ADAM9 expression correlated with immunosuppressive microenvironments, characterized by increased M2 macrophages, neutrophils. Single\u2212cell analysis identified predominant enrichment of ADAM9 in M2 macrophage subsets. Pseudotime trajectory analysis linked ADAM9 expression to M2 macrophage differentiation, while cell\u2212cell interaction studies revealed ADAM9\u2212high M2 macrophages as key signaling hubs in the tumor microenvironment.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments demonstrated that ADAM9 silencing regulated efferocytosis and polarization in M2 macrophages, and subsequently suppressed tumor cell proliferation and migration via the IL-6\/STAT3 signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study innovatively constructed a robust prognostic model based on ERG signatures. ERG signatures including ADAM9 not only precisely forecasted the survival outcomes and therapeutic responses of LUAD patients but also comprehensively uncovered the oncogenic role of ADAM9 in promoting tumor progression through multi-dimensional analysis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1772167","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:05:12Z","timestamp":1779689112000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics profiling identifies ADAM9 as a key efferocytosis driver in lung adenocarcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Guofu","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]},{"name":"Respiratory Disease Research Institute, the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanlan","family":"Lin","sequence":"additional","affiliation":[{"name":"The School of Medical Technology and Engineering, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]},{"name":"Respiratory Disease Research Institute, the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gongping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]},{"name":"Respiratory Disease Research Institute, the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA: A Cancer J For Clin"},{"key":"B2","doi-asserted-by":"publisher","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: A Cancer J For Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00312-3","article-title":"Lung cancer","volume":"398","author":"Thai","year":"2021","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"796","DOI":"10.21147\/j.issn.1000-9604.2025.05.11","article-title":"Molecular subtypes and prognostic signature rooted in disulfidptosis highlight tumor microenvironment in lung adenocarcinoma","volume":"37","author":"Xia","year":"2025","journal-title":"Chin J Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.04.018","article-title":"Living on the edge: Efferocytosis at the interface of homeostasis and pathology","volume":"50","author":"Morioka","year":"2019","journal-title":"Immunity"},{"key":"B6","article-title":"Efferocytosis and the story of \"Find Me,\" \"Eat Me,\" and \"Don't Eat Me\" signaling in the tumor microenvironment","volume":"1329","author":"Banerjee","year":"2021"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-326350","article-title":"PD-L1 blockade liberates intrinsic antitumorigenic properties of glycolytic macrophages in hepatocellular carcinoma","volume":"71","author":"Lu","year":"2022","journal-title":"Gut"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.mct-21-0915","article-title":"Preclinical evaluation of IMGC936, a next-generation maytansinoid-based antibody-drug conjugate targeting ADAM9-expressing tumors","volume":"21","author":"Scribner","year":"2022","journal-title":"Mol Cancer Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.103179","article-title":"Genetic variants of ADAM9 as potential predictors for biochemical recurrence in prostate cancer patients after receiving a radical prostatectomy","volume":"21","author":"Lin","year":"2024","journal-title":"Int J Med Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/biom12060791","article-title":"Relevance of a disintegrin and metalloproteinase domain-containing (ADAM)9 protein expression to bladder cancer Malignancy","volume":"12","author":"Moriwaki","year":"2022","journal-title":"Biomolecules"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.1038\/s41467-024-48524-6","article-title":"ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection","volume":"15","author":"Bazzone","year":"2024","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"26862","DOI":"10.1038\/s41598-024-76049-x","article-title":"A pan-cancer study of ADAM9's immunological function and prognostic value particularly in liver cancer","volume":"14","author":"AmeliMojarad","year":"2024","journal-title":"Sci Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.62347\/lodv2387","article-title":"ADAM9 drives the immunosuppressive microenvironment by cholesterol biosynthesis-mediated activation of IL6-STAT3 signaling for lung tumor progression","volume":"14","author":"Liu","year":"2024","journal-title":"Am J Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-3578-9_6","article-title":"A practical guide to The Cancer Genome Atlas (TCGA)","volume":"1418","author":"Wang","year":"2016","journal-title":"Methods Mol Biol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1.30.31","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From gene data mining to disease genome sequence analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr Protoc Bioinf"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.32604\/or.2023.028051","article-title":"Solute carrier-related signature for assessing prognosis and immunity in patients with clear-cell renal cell carcinoma","volume":"31","author":"Bao","year":"2023","journal-title":"Oncol Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106201","article-title":"A network pharmacology approach to explore the potential targets underlying the effect of sinomenine on rheumatoid arthritis","volume":"80","author":"Guo","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"5042","DOI":"10.1038\/ncomms6042","article-title":"Dax1 and Nanog act in parallel to stabilize mouse embryonic stem cells and induced pluripotency","volume":"5","author":"Zhang","year":"2014","journal-title":"Nat Commun"},{"key":"B19","doi-asserted-by":"publisher","first-page":"324","DOI":"10.4049\/jimmunol.212.supp.0440.4990","article-title":"Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice","volume":"15","author":"Grazda","year":"2024","journal-title":"Cell Death Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-004863","article-title":"Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects","volume":"10","author":"Peters","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2022.09.109","article-title":"Predictive biomarkers for immunotherapy in lung cancer: Perspective from the International Association for the Study of Lung Cancer Pathology Committee","volume":"17","author":"Mino-Kenudson","year":"2022","journal-title":"J Thorac Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2025.06.11","article-title":"Metabolic reprogramming signature predicts immunotherapy efficacy in lung adenocarcinoma: Targeting SLC25A1 to overcome immune resistance","volume":"37","author":"Zhang","year":"2025","journal-title":"Chin J Cancer Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/s41746-025-02172-2","article-title":"Machine learning identifies TIME subtypes linking EGFR mutations and immune states in lung adenocarcinoma","volume":"8","author":"Gong","year":"2025","journal-title":"NPJ Dig Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.124.321189","article-title":"Platelet angiopoietin-1 protects against murine models of tumor metastasis","volume":"44","author":"Roweth","year":"2024","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107704","article-title":"Activated platelets facilitate hematogenous metastasis of breast cancer by modulating the PDGFR-\u03b2\/COX-2 axis","volume":"26","author":"Tang","year":"2023","journal-title":"iScience"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200597","article-title":"A real-time image-based efferocytosis assay for the discovery of functionally inhibitory anti-MerTK antibodies","volume":"210","author":"Bravo","year":"2023","journal-title":"J Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.3c04884","article-title":"Efferocytosis nanoinhibitors to promote secondary necrosis and potentiate the immunogenicity of conventional cancer therapies for improved therapeutic benefits","volume":"17","author":"Wu","year":"2023","journal-title":"ACS Nano"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.02.015","article-title":"Radiation-based immunogenic vaccine combined with a macrophage \"checkpoint inhibitor\" for boosting innate and adaptive immunity against metastatic colon cancers","volume":"14","author":"Xu","year":"2024","journal-title":"Acta Pharm Sin B"},{"key":"B29","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.devcel.2024.01.020","article-title":"Redistribution of the glycocalyx exposes phagocytic determinants on apoptotic cells","volume":"59","author":"Le","year":"2024","journal-title":"Dev Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1186\/s12964-024-01669-9","article-title":"Extracellular vesicles containing MFGE8 from colorectal cancer facilitate macrophage efferocytosis","volume":"22","author":"Ma","year":"2024","journal-title":"Cell Commun Signaling"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-01107-7","article-title":"Broad-spectrum antibiotics disrupt homeostatic efferocytosis","volume":"6","author":"Saavedra","year":"2024","journal-title":"Nat Metab"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00930-w","article-title":"Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling","volume":"19","author":"Kim","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202403849","article-title":"Ccl2-induced regulatory T cells balance inflammation through macrophage polarization during liver reconstitution","volume":"11","author":"Wang","year":"2024","journal-title":"Adv Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202303711","article-title":"LRRK2 Gly2019Ser mutation promotes ER stress via interacting with THBS1\/TGF-\u03b21 in Parkinson's disease","volume":"10","author":"Yao","year":"2023","journal-title":"Adv Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101698","article-title":"Uncovering therapeutic targets for macrophage-mediated T cell suppression and PD-L1 therapy sensitization","volume":"5","author":"Kumar","year":"2024","journal-title":"Cell Rep Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1093\/jimmun\/vkaf283.1385","article-title":"Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma","volume":"57","author":"De Leo","year":"2024","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-009930","article-title":"Arginase-1-specific T cells target and modulate tumor-associated macrophages","volume":"13","author":"Martinenaite","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2024.122533","article-title":"MDSC-targeting gold nanoparticles enhance PD-1 tumor immunotherapy by inhibiting NLRP3 inflammasomes","volume":"307","author":"Zhu","year":"2024","journal-title":"Biomaterials"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00691-z","article-title":"Sirp\u03b1 on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47","volume":"5","author":"Huang","year":"2024","journal-title":"Nat Cancer"},{"key":"B40","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.devcel.2024.10.010","article-title":"A subset of neutrophils activates anti-tumor immunity and inhibits non-small-cell lung cancer progression","volume":"60","author":"Tang","year":"2025","journal-title":"Dev Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2025.01.003","article-title":"IL-8 contributes to functional diversity of tumor-infiltrating neutrophils: A new target for cancer immunotherapy","volume":"60","author":"Tavukcuoglu","year":"2025","journal-title":"Dev Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0222-4","article-title":"Tumor-associated neutrophils in patients with cancer","volume":"16","author":"Shaul","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by TGF-beta: \"N1\" versus \"N2\" TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2024.03.029","article-title":"In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy","volume":"369","author":"Liu","year":"2024","journal-title":"J Controlled Rel"},{"key":"B45","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/s13045-022-01384-3","article-title":"Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma","volume":"15","author":"Tong","year":"2022","journal-title":"J Hematol Oncol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00720-x","article-title":"Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy","volume":"5","author":"Huang","year":"2024","journal-title":"Nat Cancer"},{"key":"B47","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41408-024-01133-4","article-title":"Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma","volume":"14","author":"Evers","year":"2024","journal-title":"Blood Cancer J"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701247","article-title":"The STAT3-IL-10-IL-6 pathway is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury","volume":"200","author":"Campana","year":"2018","journal-title":"J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m111.264325","article-title":"Interleukin-6 protects human macrophages from cellular cholesterol accumulation and attenuates the proinflammatory response","volume":"286","author":"Frisdal","year":"2011","journal-title":"J Biol Chem"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.7150\/thno.60040","article-title":"Converged Rab37\/IL-6 trafficking and STAT3\/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment","volume":"11","author":"Kuo","year":"2021","journal-title":"Theranostics"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1772167\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:05:13Z","timestamp":1779689113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1772167\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,25]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2026.1772167"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1772167","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,25]]},"article-number":"1772167"}}