{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:11:18Z","timestamp":1793146278367,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"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><jats:title>Background<\/jats:title><jats:p>Transmembrane emp24 domain-containing protein 2 (TMED2) is involved in the sorting and transport of proteins between the Golgi apparatus and the endoplasmic reticulum. Recent research has identified a close association between TMED2 and tumorigenesis, yet its regulatory role and underlying mechanisms in pan-cancer signaling pathways remain unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a comprehensive pan-cancer analysis of TMED2 using multiple public databases. These analyses included assessments of prognostic significance, gene mutations, pathway enrichment, single-cell sequencing analysis, immune characteristics, co-expressed gene PPI network analysis, as well as the therapeutic response of TMED2 in immunotherapy and small molecule sensitivity. Finally, we examined the role that TMED2 plays at the cellular level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results show that the mRNA levels of TMED2 differ significantly between cancerous and normal tissues and are closely associated with cancer prognosis. Specifically, in CESC, MESO, LGG, and UVM, overexpression of TMED2 correlates with patient prognosis and various clinical pathological features. TMED2 is significantly associated with immune infiltration (including endothelial cells, neutrophils, dendritic cells, and eosinophils), immune checkpoints (CD274, HAVCR2, PDCD1LG2, and SIGLEC15), and signaling pathways (cell cycle and PI3K\/Akt). Single-cell sequencing reveals that TMED2 is predominantly expressed in tumor cells of cervical cancer, glioma, and mesothelioma. Enrichment analysis shows that genes co-expressed with TMED2 are primarily involved in processes like endoplasmic reticulum stress and the ERAD pathway. Furthermore, cellular studies indicated that TMED2 expression promotes the growth, migration and invasion of glioma cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our integrated analysis suggests that targeting TMED2, along with its associated genes and signaling pathways, could represent a new strategy for cancer immune treatment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1578627","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T04:13:08Z","timestamp":1748578388000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Pan-cancer analysis of TMED2: unraveling potential immune characteristics and prognostic value in cancer therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Zhuangzhi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changning","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouyang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchao","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3670","article-title":"Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy","volume":"14","author":"Coulie","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/B978-0-12-800267-4.00003-1","article-title":"Recognition of tumors by the innate immune system and natural killer cells","volume":"122","author":"Marcus","year":"2014","journal-title":"Adv Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103849","article-title":"Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia","volume":"365","author":"Porter","year":"2011","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune checkpoint blockade: a common denominator approach to cancer therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40164-022-00277-y","article-title":"Heterogeneity of the tumor immune microenvironment and its clinical relevance","volume":"11","author":"Jia","year":"2022","journal-title":"Exp Hematol Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13045-015-0230-5","article-title":"Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity","volume":"9","author":"Chen","year":"2016","journal-title":"J Hematol Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1590\/1678-7757-2024-0305","article-title":"Study of the role of transmembrane emp24 domain-containing protein 2 in oral squamous cell carcinoma","volume":"33","author":"Zhao-Wei","year":"2025","journal-title":"J Appl  Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S327367","article-title":"Multi-omics analysis identified TMED2 as a shared potential biomarker in six subtypes of human cancer","volume":"14","author":"Sial","year":"2021","journal-title":"Int J Gen Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1017\/S0016672319000090","article-title":"Transmembrane emp24 domain proteins in development and disease","volume":"101","author":"Aber","year":"2019","journal-title":"Genet Res (Camb)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1016\/j.devcel.2022.09.004","article-title":"ER-Golgi-localized proteins TMED2 and TMED10 control the formation of plasma membrane lipid nanodomains","volume":"57","author":"Anwar","year":"2022","journal-title":"Dev Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.08.023","article-title":"3D Structure and Interaction of p24beta and p24delta Golgi Dynamics Domains: Implication for p24 Complex Formation and Cargo Transport","volume":"428","author":"Nagae","year":"2016","journal-title":"J Mol Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001596","article-title":"TMED2 binding restricts SMO to the ER and Golgi compartments","volume":"20","author":"Di Minin","year":"2022","journal-title":"PloS Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.112.4.537","article-title":"Intracellular localization and in vivo trafficking of p24A and p23","volume":"112","author":"Blum","year":"1999","journal-title":"J Cell Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)01079-1","article-title":"The mechanisms of vesicle budding and fusion","volume":"116","author":"Bonifacino","year":"2004","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"798","DOI":"10.2174\/138620710792927420","article-title":"Discovery of novel cell proliferation-enhancing gene by random siRNA library based combinatorial screening","volume":"13","author":"Xiong","year":"2010","journal-title":"Comb Chem High Throughput Screen"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.21593","article-title":"TMED2 promotes epithelial ovarian cancer growth","volume":"8","author":"Shi-Peng","year":"2017","journal-title":"Oncotarget"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S192949","article-title":"Increased expression of TMED2 is an unfavorable prognostic factor in patients with breast cancer","volume":"11","author":"Lin","year":"2019","journal-title":"Cancer Manag Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.895281","article-title":"TMED2\/9\/10 serve as biomarkers for poor prognosis in head and neck squamous carcinoma","volume":"13","author":"Gao","year":"2022","journal-title":"Front Genet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.21037\/atm-22-5444","article-title":"Screening of the novel immune-suppressive biomarkers of TMED family and whether knockdown of TMED2\/3\/4\/9 inhibits cell migration and invasion in breast cancer","volume":"10","author":"Fang","year":"2022","journal-title":"Ann Transl Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"100910","DOI":"10.1016\/j.crmeth.2024.100910","article-title":"Enhancing immuno-oncology investigations through multidimensional decoding of tumor microenvironment with IOBR 2.0","volume":"4","author":"Zeng","year":"2024","journal-title":"Cell Rep Methods"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics: A J Integr Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-21-0433","article-title":"SMARCA4: implications of an altered chromatin-remodeling gene for cancer development and therapy","volume":"20","author":"Mardinian","year":"2021","journal-title":"Mol Cancer Ther"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.v14.10","article-title":"O-GlcNAcylation promotes Malignancy and cisplatin resistance of lung cancer by stabilising NRF2","volume":"14","author":"Zhang","year":"2024","journal-title":"Clin Transl Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"41","DOI":"10.20517\/cdr.2024.123","article-title":"NFE2L2 and ferroptosis resistance in cancer therapy","volume":"7","author":"Tang","year":"2024","journal-title":"Cancer Drug Resist"},{"key":"B25","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1615\/CritRevEukaryotGeneExpr.2021041271","article-title":"LGR6 acts as an oncogene and induces proliferation and migration of gastric cancer cells","volume":"32","author":"Fan","year":"2022","journal-title":"Crit Rev Eukaryot Gene Expr"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1212476","article-title":"Cancer immunotherapies: advances and bottlenecks","volume":"14","author":"Rui","year":"2023","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6","article-title":"The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications","volume":"17","author":"Zhang","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.08.023","article-title":"A novel shark VNAR antibody-based immunotoxin targeting TROP-2 for cancer therapy","volume":"14","author":"Xi","year":"2024","journal-title":"Acta Pharm Sin B"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2478\/jtim-2023-0002","article-title":"A pan-cancer analysis of the oncogenic role of Golgi transport 1B in human tumors","volume":"11","author":"Tian","year":"2023","journal-title":"J Transl Int Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41419-025-07619-8","article-title":"ATF6\u03b1 inhibits \u0394Np63\u03b1 expression to promote breast cancer metastasis by the GRP78-AKT1-FOXO3a signaling","volume":"16","author":"Wang","year":"2025","journal-title":"Cell Death Dis"},{"key":"B31","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41368-024-00311-1","article-title":"Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma","volume":"16","author":"Xu","year":"2024","journal-title":"Int J  Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"789","DOI":"10.3390\/biom9120789","article-title":"Paclitaxel's mechanistic and clinical effects on breast cancer","volume":"9","author":"Abu Samaan","year":"2019","journal-title":"Biomolecules"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1021\/jm9007533","article-title":"Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor","volume":"52","author":"Chao","year":"2009","journal-title":"J Med Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nat Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/s13046-021-01987-7","article-title":"Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer","volume":"40","author":"Zhang","year":"2021","journal-title":"J Exp Clin Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.964442","article-title":"The role of PD-1\/PD-L1 and application of immune-checkpoint inhibitors in human cancers","volume":"13","author":"Tang","year":"2022","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"139537","DOI":"10.1016\/j.ijbiomac.2025.139537","article-title":"Anti-tumor activity of an \u03b1PD-L1-PE38 immunotoxin delivered by engineered Nissle 1917","volume":"295","author":"Li","year":"2025","journal-title":"Int J Biol Macromol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2011.212","article-title":"p24 proteins are required for secretion of Wnt ligands","volume":"12","author":"Buechling","year":"2011","journal-title":"EMBO Rep"},{"key":"B39","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1111\/j.1471-4159.2011.07173.x","article-title":"Proteinase-activated receptors, nucleotide P2Y receptors, and \u03bc-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking","volume":"117","author":"Luo","year":"2011","journal-title":"J Neurochem"},{"key":"B40","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1083\/jcb.201012074","article-title":"Sorting of GPI-anchored proteins into ER exit sites by p24 proteins is dependent on remodeled GPI","volume":"194","author":"Fujita","year":"2011","journal-title":"J Cell Biol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"130055","DOI":"10.1016\/j.ijbiomac.2024.130055","article-title":"TMED2 promotes glioma tumorigenesis by being involved in EGFR recycling transport","volume":"262","author":"Sun","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2019.06.021","article-title":"Drug databases and their contributions to drug repurposing","volume":"112","author":"Masoudi-Sobhanzadeh","year":"2020","journal-title":"Genomics"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2022.11.006","article-title":"A clinician's guide to bioinformatics for next-generation sequencing","volume":"18","author":"Larson","year":"2023","journal-title":"J Thorac Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1578627\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T04:13:09Z","timestamp":1748578389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1578627\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,30]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2025.1578627"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1578627","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,30]]},"article-number":"1578627"}}