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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Gliomas, the most common and aggressive primary tumors in the central nervous system, are characterized by high invasiveness and resistance to therapy, making them a major focus of neuro-oncology research. Although substantial progress has been achieved in elucidating their molecular underpinnings in recent years, effective treatment modalities remain limited owing to their complex pathogenesis and tumor microenvironment. Midkine (MDK), a multifunctional growth factor, has increasingly been implicated in glioma pathogenesis and biology. MDK not only contributes to tumor cell proliferation, migration, and therapy resistance, but also plays a pivotal role in modulating the tumor microenvironment. Notably, MDK functions as both an intrinsic oncogenic driver and an extrinsic modulator of the tumor microenvironment, in to the molecular mechanisms underlying glioma pathogenesis that is critical to the formulation of effective treatments, have not comprehensively reviewed. This review summarizes the roles of MDK in various signaling pathways and summarizes recent advances in unraveling the expression patterns and functional roles of MDK and their therapeutic implications and potential as treatment targets for gliomas.<\/jats:p>","DOI":"10.31083\/fbl52445","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["Glioma Pathogenesis and Treatment Modality: Novel Insights From Midkine Research"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0425-3690","authenticated-orcid":true,"given":"Tianyuan","family":"Zhao","sequence":"first","affiliation":[{"name":"School of Materials Science and Engineering, Tiangong University, 300387 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8707-1431","authenticated-orcid":true,"given":"Xuehui","family":"Pang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Tiangong University, 300387 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1916-3256","authenticated-orcid":true,"given":"Xiaonan","family":"Xi","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Tiangong University, 300387 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2568-765X","authenticated-orcid":true,"given":"Feimeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Tiangong University, 300387 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Li J, Long S, Zhang Y, Yu S, Xu H, Liang R, et al. Single-cell transcriptome sequencing reveals new epithelial-stromal associated mesenchymal-like subsets in recurrent gliomas. Acta Neuropathologica Communications. 2025; 13: 127.","DOI":"10.1186\/s40478-025-02036-6"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Stefan D, Lesueur P, Lequesne J, Feuvret L, Bronnimann C, Cast\u00e9ra M, et al. Olaparib, Temozolomide, and Concomitant Radiotherapy for Partially Resected or Biopsy-Only Glioblastoma First-Line Treatment: Results from the OLA-TMZ-RTE-01 Phase I Study. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2025; 31: 1212\u20131222.","DOI":"10.1158\/1078-0432.CCR-24-2974"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Antonica F, Santomaso L, Pernici D, Petrucci L, Aiello G, Cutarelli A, et al. A slow-cycling\/quiescent cells subpopulation is involved in glioma invasiveness. Nature Communications. 2022; 13: 4767.","DOI":"10.1038\/s41467-022-32448-0"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Ramar V, Guo S, Hudson B, Liu M. Progress in Glioma Stem Cell Research. Cancers. 2023; 16: 102.","DOI":"10.3390\/cancers16010102"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Zhang X, Li J, Huang Y, Yang A, Liu X, Luo Y, et al. Plasma extracellular vesicles from recurrent GBMs carrying LDHA to activate glioblastoma stemness by enhancing glycolysis. Theranostics. 2025; 15: 3655\u20133672.","DOI":"10.7150\/thno.102014"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nature Reviews Clinical Oncology. 2021; 18: 170\u2013186.","DOI":"10.1038\/s41571-020-00447-z"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine. 2005; 352: 987\u2013996.","DOI":"10.1056\/NEJMoa043330"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Jayaram MA, Phillips JJ. Role of the Microenvironment in Glioma Pathogenesis. Annual Review of Pathology. 2024; 19: 181\u2013201.","DOI":"10.1146\/annurev-pathmechdis-051122-110348"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. Journal of Hematology & Oncology. 2024; 17: 31.","DOI":"10.1186\/s13045-024-01544-7"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2018; 33: 152.","DOI":"10.1016\/j.ccell.2017.12.012"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Kumar A, Mohamed E, Tong S, Chen K, Mukherjee J, Lim Y, et al. CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2022; 28: 2898\u20132910.","DOI":"10.1158\/1078-0432.CCR-21-2830"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Fan X, Salford LG, Widegren B. Glioma stem cells: evidence and limitation. Seminars in Cancer Biology. 2007; 17: 214\u2013218.","DOI":"10.1016\/j.semcancer.2006.04.002"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Zhao YD, Zhang QB, Chen H, Fei XF, Shen YT, Ji XY, et al. Research on human glioma stem cells in China. Neural Regeneration Research. 2017; 12: 1918\u20131926.","DOI":"10.4103\/1673-5374.219055"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Gong A, Huang S. FoxM1 and Wnt\/\u03b2-catenin signaling in glioma stem cells. Cancer Research. 2012; 72: 5658\u20135662.","DOI":"10.1158\/0008-5472.CAN-12-0953"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Deng Y, Chen Q, Wan C, Sun Y, Huang F, Hu Y, et al. Microglia and macrophage metabolism: a regulator of cerebral gliomas. Cell & Bioscience. 2024; 14: 49.","DOI":"10.1186\/s13578-024-01231-7"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Bi J, Chowdhry S, Wu S, Zhang W, Masui K, Mischel PS. Altered cellular metabolism in gliomas - an emerging landscape of actionable co-dependency targets. Nature Reviews. Cancer. 2020; 20: 57\u201370.","DOI":"10.1038\/s41568-019-0226-5"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Deshmukh R, Allega MF, Tardito S. A map of the altered glioma metabolism. Trends in Molecular Medicine. 2021; 27: 1045\u20131059.","DOI":"10.1016\/j.molmed.2021.07.011"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Kipper FC, Kieran MW, Thomas A, Panigrahy D. Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment. Cancer Metastasis Reviews. 2022; 41: 737\u2013747.","DOI":"10.1007\/s10555-022-10041-7"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Stockhausen MT, Kristoffersen K, Poulsen HS. The functional role of Notch signaling in human gliomas. 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Frontiers in Bioscience (Landmark Edition). 2024; 29: 285.","DOI":"10.31083\/j.fbl2908285"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Nomura Y. NF-kappaB activation and IkappaB alpha dynamism involved in iNOS and chemokine induction in astroglial cells. Life Sciences. 2001; 68: 1695\u20131701.","DOI":"10.1016\/s0024-3205(01)00967-5"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Yuan F, Wang Y, Yuan L, Tang T, Ye L, Li Y, et al. EGFRvIII-positive glioblastoma contributes to immune escape and malignant progression via the c-Fos-MDK-LRP1 axis. Cell Death & Disease. 2025; 16: 453.","DOI":"10.1038\/s41419-025-07771-1"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Zhu C, Kros JM, Cheng C, Mustafa D. The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies. Neuro-oncology. 2017; 19: 1435\u20131446.","DOI":"10.1093\/neuonc\/nox081"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Hoogstrate Y, Draaisma K, Ghisai SA, van Hijfte L, Barin N, de Heer I, et al. Transcriptome analysis reveals tumor microenvironment changes in glioblastoma. Cancer Cell. 2023; 41: 678\u2013692.e7.","DOI":"10.1016\/j.ccell.2023.02.019"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Eisenbarth D, Wang YA. Glioblastoma heterogeneity at single cell resolution. Oncogene. 2023; 42: 2155\u20132165.","DOI":"10.1038\/s41388-023-02738-y"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Hern\u00e1ndez Mart\u00ednez A, Madurga R, Garc\u00eda-Romero N, Ayuso-Sacido \u00c1. Unravelling glioblastoma heterogeneity by means of single-cell RNA sequencing. Cancer Letters. 2022; 527: 66\u201379.","DOI":"10.1016\/j.canlet.2021.12.008"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Du Y, Li R, Fu D, Zhang B, Cui A, Shao Y, et al. Multi-omics technologies and molecular biomarkers in brain tumor-related epilepsy. CNS Neuroscience & Therapeutics. 2024; 30: e14717.","DOI":"10.1111\/cns.14717"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Bexell D, Svensson A, Bengzon J. Stem cell-based therapy for malignant glioma. Cancer Treatment Reviews. 2013; 39: 358\u2013365.","DOI":"10.1016\/j.ctrv.2012.06.006"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Venneti S, Thompson CB. Metabolic Reprogramming in Brain Tumors. Annual Review of Pathology. 2017; 12: 515\u2013545.","DOI":"10.1146\/annurev-pathol-012615-044329"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Kampers LFC, Metselaar DS, Vinci M, Scirocchi F, Veldhuijzen van Zanten S, Eyrich M, et al. The Complexity of Malignant Glioma Treatment. Cancers. 2025; 17: 879.","DOI":"10.3390\/cancers17050879"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer. Cancer Letters. 2004; 204: 127\u2013143.","DOI":"10.1016\/S0304-3835(03)00450-6"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Cai YQ, Lv Y, Mo ZC, Lei J, Zhu JL, Zhong QQ. Multiple pathophysiological roles of midkine in human disease. Cytokine. 2020; 135: 155242.","DOI":"10.1016\/j.cyto.2020.155242"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Dianat N, Le Viet B, Gobbo E, Auger N, Bi\u00e8che I, Bennaceur-Griscelli A, et al. Midkine lacking its last 40 amino acids acts on endothelial and neuroblastoma tumor cells and inhibits tumor development. Molecular Cancer Therapeutics. 2015; 14: 213\u2013224.","DOI":"10.1158\/1535-7163.MCT-14-0226"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Cerezo-Wallis D, Contreras-Alcalde M, Troul\u00e9 K, Catena X, Mucientes C, Calvo TG, et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nature Medicine. 2020; 26: 1865\u20131877.","DOI":"10.1038\/s41591-020-1073-3"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Zhu WW, Guo JJ, Guo L, Jia HL, Zhu M, Zhang JB, et al. Evaluation of midkine as a diagnostic serum biomarker in hepatocellular carcinoma. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2013; 19: 3944\u20133954.","DOI":"10.1158\/1078-0432.CCR-12-3363"},{"key":"ref38","unstructured":"Yu X, Zhou Z, Tang S, Zhang K, Peng X, Zhou P, et al. MDK induces temozolomide resistance in glioblastoma by promoting cancer stem-like properties. American Journal of Cancer Research. 2022; 12: 4825\u20134839."},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Catena X, Contreras-Alcalde M, Juan-Larrea N, Cerezo-Wallis D, Calvo TG, Mucientes C, et al. Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade. Nature Cancer. 2025; 6: 682\u2013701.","DOI":"10.1038\/s43018-025-00929-y"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Xi X, Ding X, Wang Q, Liu N, Wang B, Wang G, et al. Targeting the MDK\/c-Myc complex to overcome temozolomide resistance in glioma. Clinical and Translational Medicine. 2025; 15: e70359.","DOI":"10.1002\/ctm2.70359"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Bonavia R, Inda MDM, Cavenee WK, Furnari FB. Heterogeneity maintenance in glioblastoma: a social network. Cancer Research. 2011; 71: 4055\u20134060.","DOI":"10.1158\/0008-5472.CAN-11-0153"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Mathur R, Wang Q, Schupp PG, Nikolic A, Hilz S, Hong C, et al. Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective. Cell. 2024; 187: 446\u2013463.e16.","DOI":"10.1016\/j.cell.2023.12.013"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica. 2016; 131: 803\u2013820.","DOI":"10.1007\/s00401-016-1545-1"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncology. 2021; 23: 1231\u20131251.","DOI":"10.1093\/neuonc\/noab106"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for \"Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV\". Acta Neuropathologica. 2018; 136: 805\u2013810.","DOI":"10.1007\/s00401-018-1913-0"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Bunevicius A, Miller J, Parsons M. Isocitrate Dehydrogenase, Patient-Reported Outcomes, and Cognitive Functioning of Glioma Patients: a Systematic Review. Current Oncology Reports. 2020; 22: 120.","DOI":"10.1007\/s11912-020-00978-9"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Abdusalomov A, Umirzakova S, Bekmirzaev O, Dauletov A, Buriboev A, Kutlimuratov A, et al. From Anatomy to Genomics Using a Multi-Task Deep Learning Approach for Comprehensive Glioma Profiling. Bioengineering (Basel, Switzerland). 2025; 12: 979.","DOI":"10.3390\/bioengineering12090979"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Labreche K, Kinnersley B, Berzero G, Di Stefano AL, Rahimian A, Detrait I, et al. Diffuse gliomas classified by 1p\/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci. Acta Neuropathologica. 2018; 135: 743\u2013755.","DOI":"10.1007\/s00401-018-1825-z"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Luo J, Junaid M, Hamid N, Duan JJ, Yang X, Pei DS. Current understanding of gliomagenesis: from model to mechanism. International Journal of Medical Sciences. 2022; 19: 2071\u20132079.","DOI":"10.7150\/ijms.77287"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Luo J, Liu P, Lu C, Bian W, Su D, Zhu C, et al. Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish. Brain: a Journal of Neurology. 2021; 144: 615\u2013635.","DOI":"10.1093\/brain\/awaa404"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Koh L, Novera W, Lim SW, Chong YK, Pang QY, Low D, et al. Integrative multi-omics approach to targeted therapy for glioblastoma. Pharmacological Research. 2022; 182: 106308.","DOI":"10.1016\/j.phrs.2022.106308"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Lokody I. Metabolism: reprogramming metabolic flux in glioma. Nature Reviews. Cancer. 2014; 14: 706\u2013707.","DOI":"10.1038\/nrc3840"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Wu T, Zhao P, Chen Z, Ying T, Nie Z, Hua W, et al. Neuro-Cancer Interactions Shape Glioma Intratumoral Heterogeneity. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2025; 12: e06694.","DOI":"10.1002\/advs.202506694"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Huang C, Xin X, Hao X, Zhou S, Xie Z, He L, et al. Construction of a whole-brain panorama for glioma vasculature reveals tumor heterogeneity and blood-brain barrier disruption. Science Advances. 2025; 11: eadw8330.","DOI":"10.1126\/sciadv.adw8330"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Valvi S, Tsoli M, Chitranjan A, Shen H, Chang C, Kankean A, et al. Fenretinide Targets the Rtk-Pi3k Pathway in Diffuse Intrinsic Pontine Glioma (Dipg). Neuro-Oncology. 2016;18(Suppl 3):iii52\u2013iii53.","DOI":"10.1093\/neuonc\/now073.32"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Colardo M, Segatto M, Di Bartolomeo S. Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update. International Journal of Molecular Sciences. 2021; 22: 4899.","DOI":"10.3390\/ijms22094899"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"He H, Liang L, Jiang S, Liu Y, Huang J, Sun X, et al. GINS2 regulates temozolomide chemosensitivity via the EGR1\/ECT2 axis in gliomas. Cell Death & Disease. 2024; 15: 205.","DOI":"10.1038\/s41419-024-06586-w"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Beltzig L, Christmann M, Kaina B. Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics. Cells. 2022; 11: 2588.","DOI":"10.3390\/cells11162588"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Leaver HA, Rizzo MT, Whittle IR. Glioma cell death: cell-cell interactions and signalling networks. Molecular Neurobiology. 2010; 42: 89\u201396.","DOI":"10.1007\/s12035-010-8135-3"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Tyler MA, Ulasov IV, Lesniak MS. Cancer cell death by design: apoptosis, autophagy and glioma virotherapy. Autophagy. 2009; 5: 856\u2013857.","DOI":"10.4161\/auto.8792"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Spina R, Mills I, Ahmad F, Chen C, Ames HM, Winkles JA, et al. DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts. Oncogene. 2022; 41: 5361\u20135372.","DOI":"10.1038\/s41388-022-02517-1"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Han S, Liu Y, Cai SJ, Qian M, Ding J, Larion M, et al. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. British Journal of Cancer. 2020; 122: 1580\u20131589.","DOI":"10.1038\/s41416-020-0814-x"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"de Los Santos-Jim\u00e9nez J, Campos-Sandoval JA, M\u00e1rquez-Torres C, Urbano-Polo N, Br\u00f8ndegaard D, Mart\u00edn-Rufi\u00e1n M, et al. Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells. Journal of Biomedical Science. 2021; 28: 14.","DOI":"10.1186\/s12929-021-00712-y"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Tang F, Wang Y, Zeng Y, Xiao A, Tong A, Xu J. Tumor-associated macrophage-related strategies for glioma immunotherapy. NPJ Precision Oncology. 2023; 7: 78.","DOI":"10.1038\/s41698-023-00431-7"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Vandenberk L, Garg AD, Verschuere T, Koks C, Belmans J, Beullens M, et al. Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma. Oncoimmunology. 2016; 5: e1083669.","DOI":"10.1080\/2162402X.2015.1083669"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Jackson C, Cherry C, Bom S, Dykema AG, Wang R, Thompson E, et al. Distinct myeloid-derived suppressor cell populations in human glioblastoma. Science (New York, N.Y.). 2025; 387: eabm5214.","DOI":"10.1126\/science.abm5214"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Perelroizen R, Philosof B, Budick-Harmelin N, Chernobylsky T, Ron A, Katzir R, et al. Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity. 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Cancers. 2025; 17: 2630.","DOI":"10.3390\/cancers17162630"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"IDH Inhibitors Target Common Glioma Mutation. Cancer Discovery. 2019; 9: 992.","DOI":"10.1158\/2159-8290.CD-ND2019-007"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Olympios N, Gilard V, Marguet F, Clatot F, Di Fiore F, Fontanilles M. TERT Promoter Alterations in Glioblastoma: A Systematic Review. Cancers. 2021; 13: 1147.","DOI":"10.3390\/cancers13051147"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Xue S, Hu M, Iyer V, Yu J. Blocking the PD-1\/PD-L1 pathway in glioma: a potential new treatment strategy. Journal of Hematology & Oncology. 2017; 10: 81.","DOI":"10.1186\/s13045-017-0455-6"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, et al. 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Aging. 2023; 15: 5339\u20135354.","DOI":"10.18632\/aging.204752"},{"key":"ref103","doi-asserted-by":"publisher","unstructured":"Zhou Q, Yang C, Mou Z, Wu S, Dai X, Chen X, et al. Identification and validation of a poor clinical outcome subtype of primary prostate cancer with Midkine abundance. Cancer Science. 2022; 113: 3698\u20133709.","DOI":"10.1111\/cas.15546"},{"key":"ref104","doi-asserted-by":"publisher","unstructured":"Hsu YC, Luo CW, Chang SJ, Lai CY, Yang YT, Chen YZ, et al. Targeting Bmi1 for Enhancing Anoikis Sensitivity and Inhibiting Metastasis in Colorectal Cancer. Cancer Genomics & Proteomics. 2024; 21: 523\u2013532.","DOI":"10.21873\/cgp.20469"},{"key":"ref105","doi-asserted-by":"publisher","unstructured":"Cheevapruk K, Ueno M, Sungwan P, Sittithumcharee G, Kariya R, Sampattavanich S, et al. Novel Midkine Inhibitor Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma. 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