{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:09:11Z","timestamp":1777496951785,"version":"3.51.4"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82303076"],"award-info":[{"award-number":["82303076"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82472905"],"award-info":[{"award-number":["82472905"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Science & Technology Development Fund of Tianjin Education Commission for Higher Education","award":["2022KJ225"],"award-info":[{"award-number":["2022KJ225"]}]},{"name":"National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine","award":["QZ23-10"],"award-info":[{"award-number":["QZ23-10"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The role of extrachromosomal DNA (ecDNA)-related genes in osteosarcoma remains largely unexplored. The aim of this study is to investigate the association between ecDNA-related genes and prognosis and tumor microenvironment (TME) in osteosarcoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Differential gene expression analysis of GEO datasets was conducted to identify ecDNA-related genes in osteosarcoma. Based on bulk RNA-seq data, a novel ecDNA-related Gene Prognostic Score Model (EGPSM) was developed using an integrated framework of 101 machine learning algorithms, which was validated in training, testing, and external cohorts. The associations between risk scores, prognosis, and TME characteristics were comprehensively evaluated. Single-cell RNA sequencing (scRNA-seq) data were further analyzed to elucidate the relationship between EGPSM, pro-tumor behaviors, and immune modulation in osteosarcoma, as well as to identify key prognostic genes involved in tumor progression. Lastly, we conducted in vitro and in vivo assays to characterize the biological roles of MTDH and to elucidate its regulatory effects on CD8\u207a T cell function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A robust EGPSM was constructed, demonstrating superior predictive accuracy with a maximum C-index of 0.803. High-risk patients exhibited poorer survival, higher metastatic potential, and an \"immune-cold\" TME characterized by diminished CD8\u207a T\/NK cell infiltration and impaired effector functions. Single-cell analysis confirmed the enrichment of malignant cells and depletion of T\/NK populations with lower effector scores in the high-risk group. MTDH was identified as a key driver; functional assays showed it promotes proliferation and invasion while inhibiting apoptosis. Notably, MTDH knockdown potentiated CD8\u207a T-cell cytotoxicity by increasing the levels of granzyme B, IFN-\n                      <jats:italic>\u03b3<\/jats:italic>\n                      , and perforin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The newly developed EGPSM represents an effective tool for prognostic assessment and therapeutic stratification in osteosarcoma. MTDH may serve as a promising prognostic biomarker and therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-026-04383-2","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T13:22:53Z","timestamp":1777382573000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating single-cell and bulk transcriptomes to reveal prognostic and immunological features of ecDNA-related genes in osteosarcoma"],"prefix":"10.1007","volume":"75","author":[{"given":"Jinyan","family":"Feng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianchao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Houzhi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiqin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuxin","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guowen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"4383_CR1","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1038\/s41467-024-45479-6","volume":"15","author":"S Wang","year":"2024","unstructured":"Wang S, Wu CY, He MM, Yong JX, Chen YX, Qian LM et al (2024) Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer. Nat Commun 15:1515","journal-title":"Nat Commun"},{"key":"4383_CR2","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41586-020-03064-z","volume":"591","author":"O Shoshani","year":"2021","unstructured":"Shoshani O, Brunner SF, Yaeger R, Ly P, Nechemia-Arbely Y, Kim DH et al (2021) Chromothripsis drives the evolution of gene amplification in cancer. Nature 591:137\u2013141","journal-title":"Nature"},{"key":"4383_CR3","doi-asserted-by":"publisher","first-page":"6387","DOI":"10.7150\/thno.111765","volume":"15","author":"B Shi","year":"2025","unstructured":"Shi B, Yang P, Qiao H, Yu D, Zhang S (2025) Extrachromosomal circular DNA drives dynamic genome plasticity: emerging roles in disease progression and clinical potential. Theranostics 15:6387\u20136411","journal-title":"Theranostics"},{"key":"4383_CR4","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/s41586-024-07861-8","volume":"635","author":"KL Hung","year":"2024","unstructured":"Hung KL, Jones MG, Wong IT, Curtis EJ, Lange JT, He BJ et al (2024) Coordinated inheritance of extrachromosomal DNAs in cancer cells. Nature 635:201\u2013209","journal-title":"Nature"},{"key":"4383_CR5","doi-asserted-by":"crossref","unstructured":"Haughey M, Noorani I, Swanton C, Mischel PS, Werner B (2025) Extrachromosomal DNA: shaping the evolutionary dynamics of cancer. Trends Cancer","DOI":"10.1016\/j.trecan.2025.06.004"},{"key":"4383_CR6","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/s41586-024-08107-3","volume":"635","author":"C Bailey","year":"2024","unstructured":"Bailey C, Pich O, Thol K, Watkins TBK, Luebeck J, Rowan A et al (2024) Origins and impact of extrachromosomal DNA. Nature 635:193\u2013200","journal-title":"Nature"},{"issue":"6","key":"4383_CR7","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1158\/2159-8290.CD-24-1532","volume":"15","author":"W Lv","year":"2025","unstructured":"Lv W, Zeng Y, Li C, Liang Y, Tao H, Zhu Y, Sui X, Li Y, Jiang S, Gao Q, Rodriguez-Fos E (2025) Spatial\u2013temporal diversity of extrachromosomal DNA shapes urothelial carcinoma evolution and the tumor immune microenvironment. Cancer Discov 15(6):1225\u20131246","journal-title":"Cancer Discov"},{"key":"4383_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57447-9","volume":"16","author":"T Nakagawa","year":"2025","unstructured":"Nakagawa T, Luebeck J, Zhu K, Lange JT, Sasik R, Phillips C et al (2025) Inhibition of human-HPV hybrid ecDNA enhancers reduces oncogene expression and tumor growth in oropharyngeal cancer. Nat Commun 16:2964","journal-title":"Nat Commun"},{"key":"4383_CR9","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/s41586-025-08721-9","volume":"640","author":"E Fiorini","year":"2025","unstructured":"Fiorini E, Malinova A, Schreyer D, Pasini D, Bevere M, Alessio G et al (2025) MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC. Nature 640:811\u2013820","journal-title":"Nature"},{"key":"4383_CR10","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nature25459","volume":"554","author":"S Mueller","year":"2018","unstructured":"Mueller S, Engleitner T, Maresch R, Zukowska M, Lange S, Kaltenbacher T et al (2018) Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554:62\u201368","journal-title":"Nature"},{"key":"4383_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08200-y","volume":"10","author":"V Deshpande","year":"2019","unstructured":"Deshpande V, Luebeck J, Nguyen ND, Bakhtiari M, Turner KM, Schwab R et al (2019) Exploring the landscape of focal amplifications in cancer using AmpliconArchitect. Nat Commun 10:392","journal-title":"Nat Commun"},{"key":"4383_CR12","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/s41588-020-0678-2","volume":"52","author":"H Kim","year":"2020","unstructured":"Kim H, Nguyen NP, Turner K, Wu S, Gujar AD, Luebeck J et al (2020) Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat Genet 52:891\u2013897","journal-title":"Nat Genet"},{"key":"4383_CR13","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/s41586-024-07802-5","volume":"635","author":"J Tang","year":"2024","unstructured":"Tang J, Weiser NE, Wang G, Chowdhry S, Curtis EJ, Zhao Y et al (2024) Enhancing transcription-replication conflict targets ecDNA-positive cancers. Nature 635:210\u2013218","journal-title":"Nature"},{"key":"4383_CR14","doi-asserted-by":"publisher","first-page":"3090","DOI":"10.1016\/j.molcel.2025.07.007","volume":"85","author":"LN Qin","year":"2025","unstructured":"Qin LN, Wu T, Zhen XT, Zhao YL, Zhou JS, Cheng SB et al (2025) Extrachromosomal DNA biogenesis is dependent on DNA looping and religation by YY1-Lig3-PARylation complex. Mol Cell 85:3090\u2013107.e11","journal-title":"Mol Cell"},{"key":"4383_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61558-8","volume":"16","author":"W Jawhar","year":"2025","unstructured":"Jawhar W, Danieau G, Annett A, Ishii T, Bajic A, Castillo-Orozco A et al (2025) Aberrant EZHIP expression drives tumorigenesis in osteosarcoma. Nat Commun 16:6752","journal-title":"Nat Commun"},{"key":"4383_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.148083","volume":"330","author":"P Jang","year":"2025","unstructured":"Jang P, Luo C, Chen M, Peng Y, Lu T, Wang X et al (2025) Integrative bioinformatics and experimental validation identify pyrroline-5-carboxylate reductase 1 as a mitochondrial regulator and diagnostic biomarker in osteosarcoma. Int J Biol Macromol 330:148083","journal-title":"Int J Biol Macromol"},{"key":"4383_CR17","doi-asserted-by":"crossref","unstructured":"Du M, Zhang X, Cong M, Cai C, Zhang Q, Xin H, et al. CircYAP1 inhibits osteosarcoma progression through the miR-135b-5p\/FRK axis. iScience. 2025; 28: 112858.","DOI":"10.1016\/j.isci.2025.112858"},{"key":"4383_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1394339","volume":"12","author":"H Liang","year":"2024","unstructured":"Liang H, Cui M, Tu J, Chen X (2024) Advancements in osteosarcoma management: integrating immune microenvironment insights with immunotherapeutic strategies. Frontiers in Cell and Developmental Biology 12:1394339","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"4383_CR19","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.1200\/JCO-24-01281","volume":"43","author":"H Hiraga","year":"2025","unstructured":"Hiraga H, Machida R, Kawai A, Kunisada T, Yonemoto T, Endo M et al (2025) Methotrexate, Doxorubicin, and Cisplatin versus Methotrexate, Doxorubicin, and Cisplatin + Ifosfamide in poor responders to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (JCOG0905): A multicenter, open-label, randomized trial. J Clin Oncol 43:1886\u20131897","journal-title":"J Clin Oncol"},{"key":"4383_CR20","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41413-024-00359-z","volume":"12","author":"RA Lacinski","year":"2024","unstructured":"Lacinski RA, Dziadowicz SA, Melemai VK, Fitzpatrick B, Pisquiy JJ, Heim T et al (2024) Spatial multiplexed immunofluorescence analysis reveals coordinated cellular networks associated with overall survival in metastatic osteosarcoma. Bone Res 12:55","journal-title":"Bone Res"},{"key":"4383_CR21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1579822","volume":"16","author":"Z Han","year":"2025","unstructured":"Han Z, Chen G, Wang D (2025) Emerging immunotherapies in osteosarcoma: from checkpoint blockade to cellular therapies. Front Immunol 16:1579822","journal-title":"Front Immunol"},{"key":"4383_CR22","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-024-02105-9","volume":"23","author":"S Yu","year":"2024","unstructured":"Yu S, Yao X (2024) Advances on immunotherapy for osteosarcoma. Mol Cancer 23:192","journal-title":"Mol Cancer"},{"key":"4383_CR23","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.celrep.2014.03.003","volume":"7","author":"X Chen","year":"2014","unstructured":"Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E et al (2014) Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7:104\u2013112","journal-title":"Cell Rep"},{"key":"4383_CR24","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature25480","volume":"555","author":"SN Gr\u00f6bner","year":"2018","unstructured":"Gr\u00f6bner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA et al (2018) The landscape of genomic alterations across childhood cancers. Nature 555:321\u2013327","journal-title":"Nature"},{"key":"4383_CR25","doi-asserted-by":"crossref","unstructured":"Pasic I, Shlien A, Durbin AD, Stavropoulos DJ, Baskin B, Ray PN, et al. Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding RNAs and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma. Cancer Res. 2010; 70: 160\u201371.","DOI":"10.1158\/0008-5472.CAN-09-1902"},{"key":"4383_CR26","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.709210","volume":"11","author":"Y Liu","year":"2021","unstructured":"Liu Y, Feng W, Dai Y, Bao M, Yuan Z, He M et al (2021) Single-cell transcriptomics reveals the complexity of the tumor microenvironment of treatment-naive Osteosarcoma. Front Oncol 11:709210","journal-title":"Front Oncol"},{"key":"4383_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216594","volume":"582","author":"W Hong","year":"2024","unstructured":"Hong W, Zhang Y, Wang S, Zheng D, Hsu S, Zhou J et al (2024) Deciphering the immune modulation through deep transcriptomic profiling and therapeutic implications of DNA damage repair pattern in hepatocellular carcinoma. Cancer Lett 582:216594","journal-title":"Cancer Lett"},{"key":"4383_CR28","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s12935-025-03775-1","volume":"25","author":"J Nie","year":"2025","unstructured":"Nie J, Wang S, Zhong Y, Yang F, Liu J, Liu Z (2025) Identifying PSIP1 as a critical R-loop regulator in osteosarcoma via machine-learning and multi-omics analysis. Cancer Cell Int 25:159","journal-title":"Cancer Cell Int"},{"key":"4383_CR29","doi-asserted-by":"publisher","first-page":"2798","DOI":"10.1016\/j.csbj.2024.06.035","volume":"23","author":"H Liu","year":"2024","unstructured":"Liu H, Zhang W, Zhang Y, Adegboro AA, Fasoranti DO, Dai L et al (2024) Mime: A flexible machine-learning framework to construct and visualize models for clinical characteristics prediction and feature selection. Comput Struct Biotechnol J 23:2798\u20132810","journal-title":"Comput Struct Biotechnol J"},{"key":"4383_CR30","doi-asserted-by":"publisher","first-page":"4162","DOI":"10.3758\/s13428-024-02356-w","volume":"56","author":"R Th\u00e9riault","year":"2024","unstructured":"Th\u00e9riault R, Ben-Shachar MS, Patil I, L\u00fcdecke D, Wiernik BM, Makowski D (2024) Check your outliers! An introduction to identifying statistical outliers in R with easystats. Behav Res Methods 56:4162\u20134172","journal-title":"Behav Res Methods"},{"key":"4383_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.934494","volume":"13","author":"C Zhao","year":"2022","unstructured":"Zhao C, Xiong K, Adam A, Ji Z, Li X (2022) Necroptosis identifies novel molecular phenotypes and influences tumor immune microenvironment of Lung Adenocarcinoma. Front Immunol 13:934494","journal-title":"Front Immunol"},{"key":"4383_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20059-6","volume":"11","author":"Y Zhou","year":"2020","unstructured":"Zhou Y, Yang D, Yang Q, Lv X, Huang W, Zhou Z et al (2020) Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat Commun 11:6322","journal-title":"Nat Commun"},{"key":"4383_CR33","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1186\/s12967-025-06346-0","volume":"23","author":"J Chen","year":"2025","unstructured":"Chen J, Cui N, He SH, Xia CY, Li WQ (2025) Single-cell transcriptomics reveals metabolic remodeling and functional specialization in the immune microenvironment of bone tumors. J Transl Med 23:554","journal-title":"J Transl Med"},{"key":"4383_CR34","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.apsb.2024.10.016","volume":"15","author":"J Sun","year":"2025","unstructured":"Sun J, Yuan H, Sun L, Zhao L, Wang Y, Hou C et al (2025) Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8(+) T-cell-mediated antitumor immunity in liver cancer. Acta Pharm Sin B 15:188\u2013204","journal-title":"Acta Pharm Sin B"},{"key":"4383_CR35","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1038\/s41401-024-01263-2","volume":"45","author":"LL Sun","year":"2024","unstructured":"Sun LL, Zhao LN, Sun J, Yuan HF, Wang YF, Hou CY et al (2024) Inhibition of USP7 enhances CD8(+) T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation. Acta Pharmacol Sin 45:1686\u20131700","journal-title":"Acta Pharmacol Sin"},{"key":"4383_CR36","doi-asserted-by":"publisher","first-page":"2447","DOI":"10.1038\/s41588-024-01949-7","volume":"56","author":"H Kim","year":"2024","unstructured":"Kim H, Kim S, Wade T, Yeo E, Lipsa A, Golebiewska A et al (2024) Mapping extrachromosomal DNA amplifications during cancer progression. Nat Genet 56:2447\u20132454","journal-title":"Nat Genet"},{"key":"4383_CR37","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/S1470-2045(18)30742-3","volume":"20","author":"F Duffaud","year":"2019","unstructured":"Duffaud F, Mir O, Boudou-Rouquette P, Piperno-Neumann S, Penel N, Bompas E et al (2019) Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol 20:120\u2013133","journal-title":"Lancet Oncol"},{"key":"4383_CR38","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1158\/2159-8290.CD-17-1152","volume":"9","author":"LC Sayles","year":"2019","unstructured":"Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY et al (2019) Genome-Informed Targeted Therapy for Osteosarcoma. Cancer Discov 9:46\u201363","journal-title":"Cancer Discov"},{"key":"4383_CR39","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41568-024-00669-8","volume":"24","author":"X Yan","year":"2024","unstructured":"Yan X, Mischel P, Chang H (2024) Extrachromosomal DNA in cancer. Nat Rev Cancer 24:261\u2013273","journal-title":"Nat Rev Cancer"},{"key":"4383_CR40","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/s41576-022-00521-5","volume":"23","author":"E Yi","year":"2022","unstructured":"Yi E, Chamorro Gonz\u00e1lez R, Henssen AG, Verhaak RGW (2022) Extrachromosomal DNA amplifications in cancer. Nat Rev Genet 23:760\u2013771","journal-title":"Nat Rev Genet"},{"key":"4383_CR41","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.cell.2024.12.005","volume":"188","author":"J Espejo Valle-Inclan","year":"2025","unstructured":"Espejo Valle-Inclan J, De Noon S, Trevers K, Elrick H, van Belzen I, Zumalave S et al (2025) Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution. Cell 188:352\u201370.e22","journal-title":"Cell"},{"key":"4383_CR42","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/j.trecan.2022.04.011","volume":"8","author":"Y Zhu","year":"2022","unstructured":"Zhu Y, Gong L, Wei CL (2022) Guilt by association: EcDNA as a mobile transactivator in cancer. Trends Cancer 8:747\u2013758","journal-title":"Trends Cancer"},{"key":"4383_CR43","doi-asserted-by":"crossref","unstructured":"Oak N, Chen W, Blake A, Harrison L, O'Brien M, Previti C, et al. (2025) Investigation of DNA damage response genes validates the role of DNA repair in pediatric cancer risk and identifies SMARCAL1 as novel osteosarcoma predisposition gene. J Clin Oncol. 101200jco2501114.","DOI":"10.1200\/JCO-25-01114"},{"key":"4383_CR44","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412014","volume":"12","author":"L Li","year":"2025","unstructured":"Li L, Rong G, Gao X, Cheng Y, Sun Z, Cai X et al (2025) Bone-Targeted Fluoropeptide Nanoparticle Inhibits NF-\u03baB Signaling to Treat Osteosarcoma and Tumor-Induced Bone Destruction. Adv Sci (Weinh) 12:e2412014","journal-title":"Adv Sci (Weinh)"},{"key":"4383_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156464","volume":"139","author":"X Yuan","year":"2025","unstructured":"Yuan X, Yu S, Lin L, Chen Y, Wu Z, Fang X et al (2025) Brusatol inhibits malignant phenotypes and lipid metabolism of osteosarcoma cells by regulating PI3K\/AKT and MAPK pathways. Phytomedicine 139:156464","journal-title":"Phytomedicine"},{"key":"4383_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-025-07128-4","volume":"23","author":"X Yuan","year":"2025","unstructured":"Yuan X, Yu S, Zeng Z, Yi L, Yu B, Zhu L (2025) Hispidulin suppresses osteosarcoma by directly targeting FABP4 to disrupt lipid metabolism and inhibit the PI3K\/AKT pathway. J Transl Med 23:1062","journal-title":"J Transl Med"},{"issue":"21","key":"4383_CR47","doi-asserted-by":"publisher","first-page":"4529","DOI":"10.1158\/1078-0432.CCR-24-3399","volume":"31","author":"J Zhang","year":"2025","unstructured":"Zhang J, Jin Y, Lin H, Deng J, Ju Y, Hu X, She J, Liang Z, Dai K, Qiu M, Sun K (2025) Amplification of extrachromosomal MYC paralogs shapes immunosuppressive tumor microenvironment in small cell lung cancer. Clinical Cancer Res 31(21):4529\u20134542","journal-title":"Clinical Cancer Res"},{"key":"4383_CR48","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/j.trecan.2025.06.004","volume":"11","author":"M Haughey","year":"2025","unstructured":"Haughey M, Noorani I, Swanton C, Mischel PS, Werner B (2025) Extrachromosomal DNA: shaping the evolutionary dynamics of cancer. Trends Cancer 11:901\u2013916","journal-title":"Trends Cancer"},{"key":"4383_CR49","volume":"1878","author":"L Zhao","year":"2023","unstructured":"Zhao L, Jiang Y, Lei X, Yang X (2023) Amazing roles of extrachromosomal DNA in cancer progression. Biochimica et Biophysica Acta (BBA) 1878:188843","journal-title":"Biochimica et Biophysica Acta (BBA)"},{"key":"4383_CR50","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35628","volume":"131","author":"E Palmerini","year":"2025","unstructured":"Palmerini E, Lopez Pousa A, Grignani G, Redondo A, Hindi N, Provenzano S et al (2025) Nivolumab and sunitinib in patients with advanced bone sarcomas: A multicenter, single-arm, phase 2 trial. Cancer 131:e35628","journal-title":"Cancer"},{"key":"4383_CR51","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-023-11390-4","volume":"23","author":"L Xie","year":"2023","unstructured":"Xie L, Liang X, Xu J, Sun X, Liu K, Sun K et al (2023) Exploratory study of an anti-PD-L1\/TGF-\u03b2 antibody, TQB2858, in patients with refractory or recurrent osteosarcoma and alveolar soft part sarcoma: a report from Chinese sarcoma study group (TQB2858-Ib-02). BMC Cancer 23:868","journal-title":"BMC Cancer"},{"issue":"3","key":"4383_CR52","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008744","volume":"12","author":"M Yankelevich","year":"2024","unstructured":"Yankelevich M, Thakur A, Modak S, Chu R, Taub J, Martin A, Schalk D, Schienshang A, Whitaker S, Rea K, Lee DW (2024) Targeting refractory\/recurrent neuroblastoma and osteosarcoma with anti-CD3\u00d7 anti-GD2 bispecific antibody armed T cells. J Immunother Cancer 12(3):e008744","journal-title":"J Immunother Cancer"},{"key":"4383_CR53","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1007\/s11427-024-2710-3","volume":"68","author":"H Zhu","year":"2025","unstructured":"Zhu H, Huangfu L, Chen J, Ji J, Xing X (2025) Exploring the potential of extrachromosomal DNA as a novel oncogenic driver. Sci China Life Sci 68:144\u2013157","journal-title":"Sci China Life Sci"},{"key":"4383_CR54","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-07530-8","volume":"12","author":"T Wu","year":"2022","unstructured":"Wu T, Wu C, Zhao X, Wang G, Ning W, Tao Z et al (2022) Extrachromosomal DNA formation enables tumor immune escape potentially through regulating antigen presentation gene expression. Sci Rep 12:3590","journal-title":"Sci Rep"},{"key":"4383_CR55","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1419040","volume":"15","author":"MP Li","year":"2024","unstructured":"Li MP, Long SP, Liu WC, Long K, Gao XH (2024) EMT-related gene classifications predict the prognosis, immune infiltration, and therapeutic response of osteosarcoma. Front Pharmacol 15:1419040","journal-title":"Front Pharmacol"},{"key":"4383_CR56","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2024.14482","volume":"28","author":"L Yang","year":"2024","unstructured":"Yang L, Han M, Zhao X, Zheng L, Kong F, Zhang S et al (2024) Comprehensive pan\u2011cancer analysis of MTDH for human tumor prognosis and as an immunological biomarker including breast and kidney cancer. Oncol Lett 28:349","journal-title":"Oncol Lett"},{"issue":"5","key":"4383_CR57","doi-asserted-by":"publisher","first-page":"4694","DOI":"10.3390\/ijms24054694","volume":"24","author":"G Ortiz-Soto","year":"2023","unstructured":"Ortiz-Soto G, Babilonia-D\u00edaz NS, Lacourt-Ventura MY, Rivera-Rodr\u00edguez DM, Qui\u00f1ones-Rodr\u00edguez JI, Col\u00f3n-Vargas M, Almod\u00f3var-Rivera I, Ferrer-Torres LE, Su\u00e1rez-Arroyo IJ, Mart\u00ednez-Montemayor MM (2023) Metadherin Regulates Inflammatory Breast Cancer Invasion and Metastasis. Intern J Molecular Sci 24(5):4694","journal-title":"Intern J Molecular Sci"},{"key":"4383_CR58","doi-asserted-by":"publisher","first-page":"1484226","DOI":"10.3389\/fimmu.2024.1484226","volume":"15","author":"L Yao","year":"2024","unstructured":"Yao L, Liu L, Xu W, Xi H, Lin S, Piao G et al (2024) mRNA-seq-based analysis predicts: AEG-1 is a therapeutic target and immunotherapy biomarker for pan-cancer, including OSCC. Front Immunol 15:1484226","journal-title":"Front Immunol"},{"key":"4383_CR59","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/s43018-021-00280-y","volume":"3","author":"M Shen","year":"2022","unstructured":"Shen M, Smith HA, Wei Y, Jiang YZ, Zhao S, Wang N et al (2022) Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer. Nat Cancer 3:60\u201374","journal-title":"Nat Cancer"},{"key":"4383_CR60","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s43018-021-00279-5","volume":"3","author":"M Shen","year":"2022","unstructured":"Shen M, Wei Y, Kim H, Wan L, Jiang YZ, Hang X et al (2022) Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis. Nat Cancer 3:43\u201359","journal-title":"Nat Cancer"},{"key":"4383_CR61","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1021\/jacsau.3c00573","volume":"4","author":"H Chen","year":"2024","unstructured":"Chen H, Zhan M, Zhang Y, Liu J, Wang R, An Y et al (2024) Intracellular Delivery of Stabilized Peptide Blocking MTDH-SND1 Interaction for Breast Cancer Suppression. JACS Au 4:139\u2013149","journal-title":"JACS Au"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-026-04383-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-026-04383-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-026-04383-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:05:17Z","timestamp":1777388717000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-026-04383-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":61,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["4383"],"URL":"https:\/\/doi.org\/10.1007\/s00262-026-04383-2","relation":{},"ISSN":["1432-0851"],"issn-type":[{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]},"assertion":[{"value":"15 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All the animal experiments were approved by the Ethics Committee for Animal Experiments of Tianjin Medical University Cancer Institute and Hospital (2024069).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"159"}}