{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T08:45:02Z","timestamp":1771922702583,"version":"3.50.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"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:p>\n                    Immune checkpoint blockade therapy, particularly those targeting programmed death 1\/programmed cell death ligand 1 (PD-1\/PD-L1), has been extensively employed to treat various human cancers, significantly improving clinical outcomes. Increasing evidence reveals that the therapeutic efficacy of PD-1\/PD-L1 inhibitors depends on the abundance of PD-L1 on cancer cells and tumor-associated stromal cells. Here, we demonstrated that F-box protein 9 (FBXO9) is a novel regulator of PD-L1. We found that increased expression of FBXO9 suppresses tumor growth and promotes cytotoxic T cell activation\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Mechanistically, FBXO9 directly binds to PD-L1 protein and enhances its degradation via ubiquitination, thereby impeding PD-L1 maturation and tumor immune evasion. Meanwhile, the expression of FBXO9 is decreased in pancreatic cancer tissues in comparison to normal tissues. Furthermore, FBXO9 expression correlates inversely with PD-L1 levels, with lower FBXO9 expression being associated with worse clinical outcome. These findings identify FBXO9 as a tumor suppressor via its facilitation of PD-L1 degradation, underscoring the potential of targeting FBXO9 in immunotherapeutic approaches for treating cancers, particularly in combination with anti-PD-L1 therapy.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1726825","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:36:20Z","timestamp":1768973780000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["FBXO9 promotes anti-tumor immunity via degradation of PD-L1 in pancreatic cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Tong","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Zheng","sequence":"additional","affiliation":[{"name":"Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Wang","sequence":"additional","affiliation":[{"name":"Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueshan","family":"Pan","sequence":"additional","affiliation":[{"name":"Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Life Science, Bengbu Medical University, Laboratory Animal Center","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqing","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pathology, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[{"name":"Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Ma","sequence":"additional","affiliation":[{"name":"Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University","place":["Bengbu, Anhui, China"]},{"name":"School of Clinical Medicine, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-326311","article-title":"Pancreatic cancer: an increasing global public health concern","volume":"71","author":"Cabasag","year":"2022","journal-title":"Gut"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.02.012","article-title":"Pancreatic cancer: changing epidemiology and new approaches to risk assessment, early detection, and prevention","volume":"164","author":"Stoffel","year":"2023","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-024-00535-6","article-title":"Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives","volume":"11","author":"Zhang","year":"2024","journal-title":"Mil Med Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s12943-021-01489-2","article-title":"Combination strategies with PD-1\/PD-L1 blockade: current advances and future directions","volume":"21","author":"Yi","year":"2022","journal-title":"Mol Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2147\/ott.S105862","article-title":"PD-L1 expression in human cancers and its association with clinical outcomes","volume":"9","author":"Wang","year":"2016","journal-title":"Onco Targets Ther"},{"key":"B6","doi-asserted-by":"publisher","first-page":"eade4186","DOI":"10.1126\/sciadv.ade4186","article-title":"PD-L1 methylation restricts PD-L1\/PD-1 interactions to control cancer immune surveillance","volume":"9","author":"Huang","year":"2023","journal-title":"Sci Adv"},{"key":"B7","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s13045-019-0779-5","article-title":"Immune checkpoint inhibitors of PD-L1 as cancer therapeutics","volume":"12","author":"Akinleye","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41571-022-00601-9","article-title":"Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics","volume":"19","author":"Yamaguchi","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.1588","article-title":"Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: A phase 2 randomized clinical trial","volume":"5","author":"O'Reilly","year":"2019","journal-title":"JAMA Oncol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1038\/s41467-022-29401-6","article-title":"USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy","volume":"13","author":"Xiong","year":"2022","journal-title":"Nat Commun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/s12943-023-01883-y","article-title":"Hsa_circ_0136666 stimulates gastric cancer progression and tumor immune escape by regulating the miR-375\/PRKDC Axis and PD-L1 phosphorylation","volume":"22","author":"Miao","year":"2023","journal-title":"Mol Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.semcancer.2022.11.002","article-title":"Targeting CSC-related transcription factors by E3 ubiquitin ligases for cancer therapy","volume":"87","author":"Wang","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.06.004","article-title":"Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy","volume":"86","author":"Liu","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.semcancer.2024.05.001","article-title":"p53\/MDM2 signaling pathway in aging, senescence and tumorigenesis","volume":"101","author":"Huang","year":"2024","journal-title":"Semin Cancer Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1123244","article-title":"The E3 ubiquitin ligases regulate PD-1\/PD-L1 protein levels in tumor microenvironment to improve immunotherapy","volume":"14","author":"Hou","year":"2023","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.12.032","article-title":"Emerging role of ubiquitination in the regulation of PD-1\/PD-L1 in cancer immunotherapy","volume":"29","author":"Hu","year":"2021","journal-title":"Mol Ther"},{"key":"B17","doi-asserted-by":"publisher","first-page":"6951","DOI":"10.1038\/s41467-022-34346-x","article-title":"Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation","volume":"13","author":"Shi","year":"2022","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3700","article-title":"Roles of F-box proteins in cancer","volume":"14","author":"Wang","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"B19","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s12964-025-02445-z","article-title":"F-box proteins in cancer: from cancer cells to the tumor microenvironment","volume":"23","author":"Cheng","year":"2025","journal-title":"Cell Commun Signal"},{"key":"B20","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s40779-023-00501-8","article-title":"Elevated FBXL6 activates both wild-type KRAS and mutant KRAS(G12D) and drives HCC tumorigenesis via the ERK\/mTOR\/PRELID2\/ROS axis in mice","volume":"10","author":"Xiong","year":"2023","journal-title":"Mil Med Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02468-7","article-title":"Fbxo45 promotes the Malignant development of esophageal squamous cell carcinoma by targeting GGNBP2 for ubiquitination and degradation","volume":"41","author":"Wang","year":"2022","journal-title":"Oncogene"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1596344","article-title":"F-box proteins at the crossroads of ubiquitination and tumor immunity: regulatory networks and immunotherapy strategies","volume":"16","author":"Dai","year":"2025","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916164117","article-title":"Fbxo9 functions downstream of Sox10 to determine neuron-glial fate choice in the dorsal root ganglia through Neurog2 destabilization","volume":"117","author":"Liu","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B24","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1038\/s41419-021-04115-7","article-title":"Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia","volume":"12","author":"Lai","year":"2021","journal-title":"Cell Death Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e234","DOI":"10.1038\/emm.2016.31","article-title":"F-box only protein 9 is an E3 ubiquitin ligase of PPAR\u03b3","volume":"48","author":"Lee","year":"2016","journal-title":"Exp Mol Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/stmcls\/sxae004","article-title":"Ubiquitin E3 ligase FBXO9 regulates pluripotency by targeting DPPA5 for ubiquitylation and degradation","volume":"42","author":"Swenson","year":"2024","journal-title":"Stem Cells"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.930220","article-title":"FBXO9 mediates the cancer-promoting effects of ZNF143 by degrading FBXW7 and facilitates drug resistance in hepatocellular carcinoma","volume":"12","author":"Wang","year":"2022","journal-title":"Front Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.3390\/cancers11111717","article-title":"Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia","volume":"11","author":"Hynes-Smith","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-021-07057-7","article-title":"F-box only protein 9 and its role in cancer","volume":"49","author":"Hussain","year":"2022","journal-title":"Mol Biol Rep"},{"key":"B30","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41419-024-06425-y","article-title":"FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation","volume":"15","author":"Chen","year":"2024","journal-title":"Cell Death Dis"},{"key":"B31","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s40779-023-00460-0","article-title":"Aspartoacylase suppresses prostate cancer progression by blocking LYN activation","volume":"10","author":"Weng","year":"2023","journal-title":"Mil Med Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/s41419-022-04675-2","article-title":"Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation","volume":"13","author":"Wu","year":"2022","journal-title":"Cell Death Dis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s40779-023-00500-9","article-title":"ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression","volume":"10","author":"Xu","year":"2023","journal-title":"Mil Med Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3582","article-title":"Mechanisms and function of substrate recruitment by F-box proteins","volume":"14","author":"Skaar","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.012","article-title":"T cell dysfunction in cancer","volume":"33","author":"Thommen","year":"2018","journal-title":"Cancer Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01242-2","article-title":"Improvement of the anticancer efficacy of PD-1\/PD-L1 blockade via combination therapy and PD-L1 regulation","volume":"15","author":"Wu","year":"2022","journal-title":"J Hematol Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.7150\/thno.52435","article-title":"ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation","volume":"11","author":"Chen","year":"2021","journal-title":"Theranostics"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002990","article-title":"Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART)","volume":"9","author":"Wagner","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04508-4","article-title":"Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer","volume":"603","author":"Shitara","year":"2022","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.1038\/s41467-023-38605-3","article-title":"ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy","volume":"14","author":"Xiao","year":"2023","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-21-2300","article-title":"Phosphorylation and stabilization of PD-L1 by CK2 suppresses dendritic cell function","volume":"82","author":"Zhao","year":"2022","journal-title":"Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41392-023-01450-3","article-title":"TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance","volume":"8","author":"Ma","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.06.008","article-title":"Removal of N-linked glycosylation enhances PD-L1 detection and predicts anti-PD-1\/PD-L1 therapeutic efficacy","volume":"36","author":"Lee","year":"2019","journal-title":"Cancer Cell"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0756-0","article-title":"FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells","volume":"564","author":"Meng","year":"2018","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s44319-024-00220-8","article-title":"FBXO38 is dispensable for PD-1 regulation","volume":"25","author":"Dibus","year":"2024","journal-title":"EMBO Rep"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005116","article-title":"FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer","volume":"10","author":"Liu","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112674118","article-title":"The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage","volume":"118","author":"De","year":"2021","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12632","article-title":"Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity","volume":"7","author":"Li","year":"2016","journal-title":"Nat Commun"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nature25015","article-title":"Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance","volume":"553","author":"Zhang","year":"2018","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","first-page":"9027","DOI":"10.1038\/s41467-025-64079-6","article-title":"VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization","volume":"16","author":"Su","year":"2025","journal-title":"Nat Commun"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.3390\/biom13121724","article-title":"Identification of a prognostic signature for ovarian cancer based on ubiquitin-related genes suggesting a potential role for FBXO9","volume":"13","author":"Luo","year":"2023","journal-title":"Biomolecules"},{"key":"B52","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40164-024-00497-4","article-title":"Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and impedes lung cancer metastasis","volume":"13","author":"Liu","year":"2024","journal-title":"Exp Hematol Oncol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/ncb2651","article-title":"SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2\/Tti1 degradation and promote survival in multiple myeloma","volume":"15","author":"Fernandez-Saiz","year":"2013","journal-title":"Nat Cell Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1726825\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:39:26Z","timestamp":1771918766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1726825\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2025.1726825"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1726825","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"article-number":"1726825"}}