{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:52:09Z","timestamp":1791219129138,"version":"4.1.0"},"reference-count":117,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Institutes of Health National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA266970"],"award-info":[{"award-number":["R01 CA266970"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institutes of Health National Cancer Institute","doi-asserted-by":"publisher","award":["R0 1 CA267893-01A1"],"award-info":[{"award-number":["R0 1 CA267893-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"US Department of Veterans Affairs","doi-asserted-by":"publisher","award":["VA 1 I01 BX006280-02"],"award-info":[{"award-number":["VA 1 I01 BX006280-02"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015301","name":"Texas Tech University Health Sciences Center El Paso Paul L Foster School of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009116","name":"Harvard Transdisciplinary Research in Energetics and Cancer Center, Harvard University","doi-asserted-by":"publisher","award":["RP230444"],"award-info":[{"award-number":["RP230444"]}],"id":[{"id":"10.13039\/100009116","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009116","name":"Harvard Transdisciplinary Research in Energetics and Cancer Center, Harvard University","doi-asserted-by":"publisher","award":["RP230420"],"award-info":[{"award-number":["RP230420"]}],"id":[{"id":"10.13039\/100009116","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008746","name":"National Cancer Center","doi-asserted-by":"publisher","award":["R0 1 CA267893-01A1"],"award-info":[{"award-number":["R0 1 CA267893-01A1"]}],"id":[{"id":"10.13039\/100008746","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["8211"],"award-info":[{"award-number":["8211"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019535","name":"Texas Tech University Health Sciences Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019535","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Cancer Letters"],"published-print":{"date-parts":[[2026,3]]},"DOI":"10.1016\/j.canlet.2026.218258","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:02:16Z","timestamp":1768953736000},"page":"218258","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":16,"special_numbering":"C","title":["Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target"],"prefix":"10.1016","volume":"641","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4309-9560","authenticated-orcid":false,"given":"Hareesh B.","family":"Nair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Guang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dileep K.","family":"Vijayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramadevi","family":"Subramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajkumar","family":"Lakshmanaswamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suryavathi","family":"Viswanadhapalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangadhara R.","family":"Sareddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surinder K.","family":"Batra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratna K.","family":"Vadlamudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.canlet.2026.218258_bib1","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/S0006-291X(88)80505-9","article-title":"cDNA cloning and sequencing of a new gene intensely expressed in early differentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis","volume":"151","author":"Kadomatsu","year":"1988","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib2","first-page":"1494","article-title":"Midkine (MK): a retinoic acid-responsive, heparin-binding growth factor in relationship with differentiation, development, cancer and neural function","volume":"65","author":"Muramatsu","year":"1993","journal-title":"Seikagaku"},{"key":"10.1016\/j.canlet.2026.218258_bib3","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1083\/jcb.110.3.607","article-title":"A retinoic acid responsive gene MK found in the teratocarcinoma system is expressed in spatially and temporally controlled manner during mouse embryogenesis","volume":"110","author":"Kadomatsu","year":"1990","journal-title":"J. Cell Biol."},{"key":"10.1016\/j.canlet.2026.218258_bib4","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1111\/bph.12353","article-title":"Structure and function of MDK as the basis of its pharmacological effects","volume":"171","author":"Muramatsu","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.canlet.2026.218258_bib5","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1006\/geno.1993.1359","article-title":"Midkine gene (MDK), a gene for prenatal differentiation and neuroregulation, maps to band 11p11.2 by fluorescence in situ hybridization","volume":"17","author":"Kaname","year":"1993","journal-title":"Genomics"},{"key":"10.1016\/j.canlet.2026.218258_bib6","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/oxfordjournals.jbchem.a123797","article-title":"Genomic structure of human midkine (MK), a retinoic acid-responsive growth\/differentiation factor","volume":"111","author":"Uehara","year":"1992","journal-title":"J. Biochem."},{"key":"10.1016\/j.canlet.2026.218258_bib7","doi-asserted-by":"crossref","first-page":"6936","DOI":"10.1093\/emboj\/16.23.6936","article-title":"Solution structure of midkine, a new heparin-binding growth factor","volume":"16","author":"Iwasaki","year":"1997","journal-title":"EMBO J."},{"key":"10.1016\/j.canlet.2026.218258_bib8","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.3748\/wjg.v12.i13.2006","article-title":"Expression of midkine and its clinical significance in esophageal squamous cell carcinoma","volume":"12","author":"Ren","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"10.1016\/j.canlet.2026.218258_bib9","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1111\/j.1349-7006.2008.00957.x","article-title":"Plasma midkine level is a prognostic factor for human neuroblastoma","volume":"99","author":"Ikematsu","year":"2008","journal-title":"Cancer Sci."},{"key":"10.1016\/j.canlet.2026.218258_bib10","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1038\/s41388-019-1124-8","article-title":"Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target","volume":"39","author":"Filippou","year":"2020","journal-title":"Oncogene"},{"key":"10.1016\/j.canlet.2026.218258_bib11","article-title":"Midkine expression as a candidate biomarker to predict the recurrence of stage IA lung adenocarcinoma","volume":"6","author":"Yang","year":"2025","journal-title":"JTO Clin. Res. Rep."},{"key":"10.1016\/j.canlet.2026.218258_bib12","first-page":"1","article-title":"Prognostic relevance of MDK and TIMP1 with immune infiltration in lung adenocarcinoma","author":"Zhu","year":"2025","journal-title":"Int. Arch. Allergy Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib13","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1007\/s12672-025-02941-1","article-title":"Midkine (MDK) in cancer and drug resistance: from inflammation to therapy","volume":"16","author":"Y\u0131ld\u0131r\u0131m","year":"2025","journal-title":"Discov. Oncol."},{"key":"10.1016\/j.canlet.2026.218258_bib14","article-title":"MDK promotes M2 macrophage polarization to remodel the tumour microenvironment in clear cell renal cell carcinoma","volume":"14","author":"Shi","year":"2024","journal-title":"Sci. Rep."},{"key":"10.1016\/j.canlet.2026.218258_bib15","doi-asserted-by":"crossref","first-page":"8447","DOI":"10.1038\/s41467-024-52615-9","article-title":"The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer","volume":"15","author":"Hu","year":"2024","journal-title":"Nat. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib16","doi-asserted-by":"crossref","DOI":"10.1038\/s41594-025-01657-8","article-title":"Midkine attenuates amyloid-\u03b2 fibril assembly and plaque formation","author":"Zaman","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"10.1016\/j.canlet.2026.218258_bib17","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1158\/1535-7163.MCT-25-0130","article-title":"The discovery and characterization of HBS-101, a novel inhibitor of midkine, as a therapeutic agent for the treatment of triple-negative breast cancer","volume":"24","author":"Mahajan","year":"2025","journal-title":"Mol. Cancer Therapeut."},{"key":"10.1016\/j.canlet.2026.218258_bib18","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/s43018-025-00929-y","article-title":"Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade","volume":"6","author":"Catena","year":"2025","journal-title":"Nat. Cancer"},{"key":"10.1016\/j.canlet.2026.218258_bib19","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1038\/s41591-020-1073-3","article-title":"Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state","volume":"26","author":"Cerezo-Wallis","year":"2020","journal-title":"Nat. Med."},{"key":"10.1016\/j.canlet.2026.218258_bib20","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1006\/bbrc.1993.1559","article-title":"Midkine is a mediator of retinoic acid induced neuronal differentiation of embryonal carcinoma cells","volume":"192","author":"Michikawa","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1242\/dev.121.1.37","article-title":"Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial\u2013mesenchymal interactions during fetal development and organogenesis","volume":"121","author":"Mitsiadis","year":"1995","journal-title":"Development"},{"key":"10.1016\/j.canlet.2026.218258_bib22","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-025-16253-5","article-title":"Coordinated changes in midkine expression and midkine-associated multiomic profile in glioma microenvironment","volume":"15","author":"Lachota","year":"2025","journal-title":"Sci. Rep."},{"key":"10.1016\/j.canlet.2026.218258_bib23","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1111\/bph.12442","article-title":"Involvement of midkine in neuroblastoma tumourigenesis","volume":"171","author":"Kishida","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.canlet.2026.218258_bib24","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1186\/s12935-021-02212-3","article-title":"Midkine promotes glioblastoma progression via PI3K\u2013Akt signaling","volume":"21","author":"Hu","year":"2021","journal-title":"Cancer Cell Int."},{"key":"10.1016\/j.canlet.2026.218258_bib25","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3390\/cells13020136","article-title":"Midkine (MDK) in hepatocellular carcinoma: more than a biomarker","volume":"13","author":"Christou","year":"2024","journal-title":"Cells"},{"key":"10.1016\/j.canlet.2026.218258_bib26","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-94272-8","article-title":"Serum midkine as non-invasive biomarker for detection and prognosis of non-small cell lung cancer","volume":"11","author":"Stern","year":"2021","journal-title":"Sci. Rep."},{"key":"10.1016\/j.canlet.2026.218258_bib27","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.3390\/cancers12092402","article-title":"Midkine is a potential therapeutic target of tumorigenesis, angiogenesis, and metastasis in non-small cell lung cancer","volume":"12","author":"Shin","year":"2020","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.canlet.2026.218258_bib28","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1016\/j.febslet.2012.07.016","article-title":"Regulation of CLL survival by hypoxia-inducible factor and its target genes","volume":"586","author":"Shachar","year":"2012","journal-title":"FEBS Lett."},{"key":"10.1016\/j.canlet.2026.218258_bib29","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1007\/s11010-022-04436-x","article-title":"CAF-derived midkine promotes EMT and cisplatin resistance by upregulating lncRNA ST7-AS1 in gastric cancer","volume":"477","author":"Yang","year":"2022","journal-title":"Mol. Cell. Biochem."},{"key":"10.1016\/j.canlet.2026.218258_bib30","doi-asserted-by":"crossref","first-page":"848","DOI":"10.5858\/2000-124-0848-IMEIHC","article-title":"Increased midkine expression in hepatocellular carcinoma","volume":"124","author":"Kato","year":"2000","journal-title":"Arch. Pathol. Lab Med."},{"key":"10.1016\/j.canlet.2026.218258_bib31","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ebiom.2017.11.020","article-title":"Midkine controls arteriogenesis by regulating the bioavailability of VEGF-A and the expression of NOS1 and NOS3","volume":"27","author":"Lautz","year":"2018","journal-title":"EBioMedicine"},{"key":"10.1016\/j.canlet.2026.218258_bib32","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.gep.2019.02.001","article-title":"Expression of the heparin-binding growth factors midkine and pleiotrophin during ocular development, Gene Expr","volume":"32","author":"Cui","year":"2019","journal-title":"Patterns"},{"key":"10.1016\/j.canlet.2026.218258_bib33","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12974-020-1709-8","article-title":"Disruption of midkine gene reduces traumatic brain injury through the modulation of neuroinflammation","volume":"17","author":"Takada","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"10.1016\/j.canlet.2026.218258_bib34","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1111\/bph.12497","article-title":"Midkine in repair of the injured nervous system","volume":"171","author":"Yoshida","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.canlet.2026.218258_bib35","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1100\/2011\/517152","article-title":"Midkine in inflammation","volume":"11","author":"Weckbach","year":"2011","journal-title":"Sci. World J."},{"key":"10.1016\/j.canlet.2026.218258_bib36","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1310094","article-title":"The role of midkine in health and disease","volume":"14","author":"Neumaier","year":"2023","journal-title":"Front. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib37","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1073\/pnas.0709592105","article-title":"Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population","volume":"105","author":"Wang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.canlet.2026.218258_bib38","doi-asserted-by":"crossref","DOI":"10.1080\/19932820.2024.2383025","article-title":"Relationship between serum midkine and omentin-1 levels and the severity of sepsis in patients and their prognostic value","volume":"19","author":"Gao","year":"2024","journal-title":"Libyan J. Med."},{"key":"10.1016\/j.canlet.2026.218258_bib39","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2020.568814","article-title":"The who, what, where, and when of a promising neurotrophic therapy for perinatal brain injury","volume":"11","author":"Ross-Munro","year":"2020","journal-title":"Front. Neurol."},{"key":"10.1016\/j.canlet.2026.218258_bib40","doi-asserted-by":"crossref","DOI":"10.3389\/fcvm.2022.1003104","article-title":"Midkine\u2014A novel player in cardiovascular diseases","volume":"9","author":"Majaj","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"10.1016\/j.canlet.2026.218258_bib41","doi-asserted-by":"crossref","first-page":"410","DOI":"10.2183\/pjab.86.410","article-title":"Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases","volume":"86","author":"Muramatsu","year":"2010","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"10.1016\/j.canlet.2026.218258_bib42","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1006\/bbrc.1995.2661","article-title":"Midkine is a heat and acid stable polypeptide capable of enhancing plasminogen activator activity and neurite outgrowth extension","volume":"216","author":"Kojima","year":"1995","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib43","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1248\/bpb.b13-00845","article-title":"Functional receptors and intracellular signal pathways of midkine (MK) and pleiotrophin (PTN)","volume":"37","author":"Xu","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"10.1016\/j.canlet.2026.218258_bib44","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1242\/jcs.013946","article-title":"Midkine and LDL receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells","volume":"120","author":"Chen","year":"2007","journal-title":"J. Cell Sci."},{"key":"10.1016\/j.canlet.2026.218258_bib45","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3389\/fonc.2012.00192","article-title":"ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers","volume":"2","author":"Wellstein","year":"2012","journal-title":"Front. Oncol."},{"key":"10.1016\/j.canlet.2026.218258_bib46","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0304-3835(03)00450-6","article-title":"Midkine and pleiotrophin in neural development and cancer","volume":"204","author":"Kadomatsu","year":"2004","journal-title":"Cancer Lett."},{"key":"10.1016\/j.canlet.2026.218258_bib47","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1158\/0008-5472.CAN-12-3070","article-title":"Midkine promotes neuroblastoma through Notch2 signaling","volume":"73","author":"Kishida","year":"2013","journal-title":"Cancer Res."},{"key":"10.1016\/j.canlet.2026.218258_bib48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1006\/bbrc.1997.6905","article-title":"Identification of heparin-binding sites in midkine and their role in neurite-promotion","volume":"236","author":"Asai","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib49","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1038\/emboj.2013.79","article-title":"Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology","volume":"32","author":"Steentoft","year":"2013","journal-title":"EMBO J."},{"key":"10.1016\/j.canlet.2026.218258_bib50","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1006\/bbrc.1996.1635","article-title":"Limited proteolysis by chymotrypsin of midkine and inhibition by heparin binding","volume":"228","author":"Matsuda","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib51","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.1016\/j.febslet.2006.06.041","article-title":"Protein tyrosine phosphatase receptor type Z is inactivated by ligand-induced oligomerization","volume":"580","author":"Fukada","year":"2006","journal-title":"FEBS Lett."},{"key":"10.1016\/j.canlet.2026.218258_bib52","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1073\/pnas.0911235107","article-title":"The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules","volume":"107","author":"Bouyain","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.canlet.2026.218258_bib53","doi-asserted-by":"crossref","first-page":"8093","DOI":"10.3390\/ijms24098093","article-title":"Protein tyrosine phosphatase receptor zeta 1 as a potential target in cancer therapy and diagnosis","volume":"24","author":"Papadimitriou","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.canlet.2026.218258_bib54","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nature22977","article-title":"Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine","volume":"546","author":"Olmeda","year":"2017","journal-title":"Nature"},{"key":"10.1016\/j.canlet.2026.218258_bib55","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.4049\/jimmunol.1102346","article-title":"Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells","volume":"188","author":"Sonobe","year":"2012","journal-title":"J. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib56","article-title":"Midkine derived from cancer-associated fibroblasts promotes cisplatin-resistance via up-regulation of lncRNA ANRIL in tumour cells","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.canlet.2026.218258_bib57","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41586-022-05289-6","article-title":"Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis","volume":"610","author":"Filliol","year":"2022","journal-title":"Nature"},{"key":"10.1016\/j.canlet.2026.218258_bib58","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.canlet.2026.218258_bib59","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/s41596-024-01045-4","article-title":"CellChat for systematic analysis of cell\u2013cell communication from single-cell transcriptomics","volume":"20","author":"Jin","year":"2025","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.canlet.2026.218258_bib60","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: new dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"10.1016\/j.canlet.2026.218258_bib61","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"10.1016\/j.canlet.2026.218258_bib62","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.cell.2024.02.009","article-title":"Embracing cancer complexity: hallmarks of systemic disease","volume":"187","author":"Swanton","year":"2024","journal-title":"Cell"},{"key":"10.1016\/j.canlet.2026.218258_bib63","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s41586-022-05672-3","article-title":"Single-cell spatial landscapes of the lung tumour immune microenvironment","volume":"614","author":"Sorin","year":"2023","journal-title":"Nature"},{"key":"10.1016\/j.canlet.2026.218258_bib64","article-title":"The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth","author":"Grant","year":"2025","journal-title":"Trends Cell Biol."},{"key":"10.1016\/j.canlet.2026.218258_bib65","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"10.1016\/j.canlet.2026.218258_bib66","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth","volume":"41","author":"De Visser","year":"2023","journal-title":"Cancer Cell"},{"key":"10.1016\/j.canlet.2026.218258_bib67","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1038\/s41423-024-01216-z","article-title":"Macrophage diversity in cancer dissemination and metastasis","volume":"21","author":"Mantovani","year":"2024","journal-title":"Cell. Mol. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib68","doi-asserted-by":"crossref","first-page":"4809","DOI":"10.3390\/ijms26104809","article-title":"Significance of midkine signaling in women's cancers: novel biomarker and therapeutic target","volume":"26","author":"Aller","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.canlet.2026.218258_bib69","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1002\/iub.2458","article-title":"Shedding more light on the role of midkine in hepatocellular carcinoma: new perspectives on diagnosis and therapy","volume":"73","author":"Gowhari Shabgah","year":"2021","journal-title":"IUBMB Life"},{"key":"10.1016\/j.canlet.2026.218258_bib70","doi-asserted-by":"crossref","DOI":"10.1002\/cti2.1230","article-title":"NKG2D and MICA\/B shedding: a \u2018tag game\u2019 between NK cells and malignant cells","volume":"9","author":"Xing","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib71","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/14397595.2016.1179860","article-title":"The growth factor midkine may play a pathophysiological role in rheumatoid arthritis","volume":"27","author":"Shindo","year":"2017","journal-title":"Mod. Rheumatol."},{"key":"10.1016\/j.canlet.2026.218258_bib72","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.ajpath.2016.12.006","article-title":"Growth factor midkine promotes T-cell activation through NFAT signaling and Th1 cell differentiation in lupus nephritis","volume":"187","author":"Masuda","year":"2017","journal-title":"Am. J. Pathol."},{"key":"10.1016\/j.canlet.2026.218258_bib73","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1038\/s41467-020-15770-3","article-title":"Midkine activation of CD8+ T cells establishes a neuron\u2013immune\u2013cancer axis responsible for low-grade glioma growth","volume":"11","author":"Guo","year":"2020","journal-title":"Nat. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib74","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1166189","article-title":"Multi-faceted role of LRP1 in the immune system","volume":"14","author":"Sizova","year":"2023","journal-title":"Front. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib75","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1546382","article-title":"Integrative single-cell and spatial transcriptomics analysis reveals MDK\u2013NCL pathway's role in shaping the immunosuppressive environment of lung adenocarcinoma","volume":"16","author":"Fu","year":"2025","journal-title":"Front. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib76","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.jhep.2021.06.023","article-title":"Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer","volume":"75","author":"Zhang","year":"2021","journal-title":"J. Hepatol."},{"key":"10.1016\/j.canlet.2026.218258_bib77","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1093\/jb\/mvt035","article-title":"The heparin-binding growth factor midkine: the biological activities and candidate receptors","volume":"153","author":"Kadomatsu","year":"2013","journal-title":"J. Biochem."},{"key":"10.1016\/j.canlet.2026.218258_bib78","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.jhep.2025.01.031","article-title":"Multiomic analysis uncovers a continuous spectrum of differentiation and Wnt-MDK-driven immune evasion in hepatoblastoma","volume":"83","author":"M\u00fcnter","year":"2025","journal-title":"J. Hepatol."},{"key":"10.1016\/j.canlet.2026.218258_bib79","article-title":"Wnt\/\u03b2-catenin up-regulates midkine expression in glioma cells","volume":"8","author":"Tang","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"10.1016\/j.canlet.2026.218258_bib80","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12943-025-02405-8","article-title":"From preneoplastic lesion to heterogeneous tumor: recent insights into hepatoblastoma biology and therapeutic opportunities","volume":"24","author":"Yang","year":"2025","journal-title":"Mol. Cancer"},{"key":"10.1016\/j.canlet.2026.218258_bib81","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.2147\/IJGM.S490409","article-title":"High midkine expression correlates with poor prognosis and immune cell infiltration in hepatocellular carcinoma","author":"Yan","year":"2025","journal-title":"Int. J. Gen. Med."},{"key":"10.1016\/j.canlet.2026.218258_bib82","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3389\/fimmu.2018.00476","article-title":"NKG2D and its ligands: one for all, all for one","volume":"9","author":"Zingoni","year":"2018","journal-title":"Front. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib83","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3390\/immuno5010009","article-title":"A concise review of the role of the NKG2D receptor and its ligands in cancer","volume":"5","author":"Boneva","year":"2025","journal-title":"Immuno"},{"key":"10.1016\/j.canlet.2026.218258_bib84","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1007\/s00262-012-1235-3","article-title":"Midkine upregulates MICA\/B expression in human gastric cancer cells and decreases natural killer cell cytotoxicity","volume":"61","author":"Zhao","year":"2012","journal-title":"Cancer Immunol. Immunother."},{"key":"10.1016\/j.canlet.2026.218258_bib85","doi-asserted-by":"crossref","first-page":"8739","DOI":"10.3390\/ijms24108739","article-title":"Role of midkine in cancer drug resistance: regulators of its expression and its molecular targeting","volume":"24","author":"Saikia","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.canlet.2026.218258_bib86","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1002\/eji.200940278","article-title":"NKG2D performs two functions in invariant NKT cells: direct TCR-independent activation of NK-like cytolysis and co-stimulation of activation by CD1d","volume":"41","author":"Kuylenstierna","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib87","doi-asserted-by":"crossref","first-page":"367","DOI":"10.3389\/fimmu.2018.00367","article-title":"The role of natural killer T cells in cancer\u2014a phenotypical and functional approach","volume":"9","author":"Krijgsman","year":"2018","journal-title":"Front. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib88","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41698-024-00522-z","article-title":"Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance","volume":"8","author":"Wang","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"10.1016\/j.canlet.2026.218258_bib89","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1016\/j.ymthe.2025.03.005","article-title":"From concept to cure: the evolution of CAR-T cell therapy","volume":"33","author":"Patel","year":"2025","journal-title":"Mol. Ther."},{"key":"10.1016\/j.canlet.2026.218258_bib90","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1126\/science.ads8473","article-title":"In vivo CAR T cell generation to treat cancer and autoimmune disease","volume":"388","author":"Hunter","year":"2025","journal-title":"Science"},{"key":"10.1016\/j.canlet.2026.218258_bib91","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/s41586-023-06243-w","article-title":"CAR T therapy beyond cancer: the evolution of a living drug","volume":"619","author":"Baker","year":"2023","journal-title":"Nature"},{"key":"10.1016\/j.canlet.2026.218258_bib92","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s40164-024-00583-7","article-title":"The development and application of CAR-NK cells for cancer therapy: current state, challenges and emerging therapeutic advances","volume":"13","author":"Yao","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"10.1016\/j.canlet.2026.218258_bib93","article-title":"Microenvironmental regulation of solid tumour resistance to CAR T cell therapy","author":"Lamplugh","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.canlet.2026.218258_bib94","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejca.2025.115263","article-title":"Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma","volume":"218","author":"Strijker","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"10.1016\/j.canlet.2026.218258_bib95","doi-asserted-by":"crossref","first-page":"5110","DOI":"10.1038\/s41467-023-40850-5","article-title":"Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors","volume":"14","author":"Xiao","year":"2023","journal-title":"Nat. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib96","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/scrt425","article-title":"Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction","volume":"5","author":"Zhao","year":"2014","journal-title":"Stem Cell Res. Ther."},{"key":"10.1016\/j.canlet.2026.218258_bib97","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1091\/mbc.E14-10-1443","article-title":"Transcriptional factor specificity protein 1 (SP1) promotes the proliferation of glioma cells by up-regulating midkine (MDK)","volume":"26","author":"Luo","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"10.1016\/j.canlet.2026.218258_bib98","doi-asserted-by":"crossref","first-page":"5018","DOI":"10.1038\/s41467-022-32673-7","article-title":"Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment","volume":"13","author":"Tang","year":"2022","journal-title":"Nat. Commun."},{"key":"10.1016\/j.canlet.2026.218258_bib99","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/cncr.22068","article-title":"Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts","volume":"107","author":"Takei","year":"2006","journal-title":"Cancer"},{"key":"10.1016\/j.canlet.2026.218258_bib100","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3390\/biomedicines12010092","article-title":"Identification of MDK as a hypoxia- and epithelial\u2013mesenchymal transition-related gene biomarker of glioblastoma based on a novel risk model and in vitro experiments","volume":"12","author":"Xia","year":"2024","journal-title":"Biomedicines"},{"key":"10.1016\/j.canlet.2026.218258_bib101","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2022.937957","article-title":"Advances in prognostic and therapeutic targets for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Hippo signaling pathway","volume":"12","author":"Mranda","year":"2022","journal-title":"Front. Oncol."},{"key":"10.1016\/j.canlet.2026.218258_bib102","first-page":"2775","article-title":"Novel midkine inhibitor iMDK inhibits tumor growth and angiogenesis in oral squamous cell carcinoma","volume":"36","author":"Masui","year":"2016","journal-title":"Anticancer Res."},{"key":"10.1016\/j.canlet.2026.218258_bib103","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s42003-024-06154-0","article-title":"Midkine promotes renal fibrosis by stabilizing C\/EBP\u03b2 to facilitate endothelial\u2013mesenchymal transition","volume":"7","author":"Xu","year":"2024","journal-title":"Commun. Biol."},{"key":"10.1016\/j.canlet.2026.218258_bib104","doi-asserted-by":"crossref","DOI":"10.1155\/2012\/781765","article-title":"Desmoplasia in pancreatic cancer: can we fight it?","volume":"2012","author":"Merika","year":"2012","journal-title":"Gastroenterol. Res. Pract."},{"key":"10.1016\/j.canlet.2026.218258_bib105","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbadis.2023.166670","article-title":"Cancer-associated fibroblasts facilitate DNA damage repair by promoting glycolysis in non-small cell lung cancer","volume":"1869","author":"Zhang","year":"2023","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"10.1016\/j.canlet.2026.218258_bib106","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41419-022-04801-0","article-title":"Midkine noncanonically suppresses AMPK activation through disrupting the LKB1\u2013STRAD\u2013Mo25 complex","volume":"13","author":"Xia","year":"2022","journal-title":"Cell Death Dis."},{"key":"10.1016\/j.canlet.2026.218258_bib107","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/ncb3039","article-title":"PGC-1\u03b1 mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis","volume":"16","author":"LeBleu","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"10.1016\/j.canlet.2026.218258_bib108","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1152\/physrev.00025.2010","article-title":"Physiological relevance of cell cycle kinases","volume":"91","author":"Malumbres","year":"2011","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.canlet.2026.218258_bib109","doi-asserted-by":"crossref","first-page":"8498","DOI":"10.1039\/c3dt50612f","article-title":"Carbon monoxide release catalysed by electron transfer: electrochemical and spectroscopic investigations of Re(bpy-R)(CO)4 complexes relevant to CO2 reduction","volume":"42","author":"Grice","year":"2013","journal-title":"Dalton Trans."},{"key":"10.1016\/j.canlet.2026.218258_bib110","doi-asserted-by":"crossref","first-page":"738","DOI":"10.3109\/08820139.2012.676122","article-title":"Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity","volume":"41","author":"Harden","year":"2012","journal-title":"Immunol. Investig."},{"key":"10.1016\/j.canlet.2026.218258_bib111","first-page":"442","article-title":"Expression of midkine in patients with acute myeloid leukemia and its significance","volume":"14","author":"Yang","year":"2006","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"10.1016\/j.canlet.2026.218258_bib112","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1111\/bph.12601","article-title":"Measuring midkine: the utility of midkine as a biomarker in cancer and other diseases","volume":"171","author":"Jones","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.canlet.2026.218258_bib113","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41420-023-01392-3","article-title":"Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration","volume":"9","author":"Ding","year":"2023","journal-title":"Cell Death Discov."},{"key":"10.1016\/j.canlet.2026.218258_bib114","first-page":"5387","article-title":"Inhibitory effect of midkine-binding peptide on tumor proliferation and migration","volume":"8","author":"Huang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"10.1016\/j.canlet.2026.218258_bib115","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.jconrel.2021.01.021","article-title":"Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively eradicate sorafenib-resistant hepatocellular carcinoma in vivo","volume":"331","author":"Younis","year":"2021","journal-title":"J. Contr. Release"},{"key":"10.1016\/j.canlet.2026.218258_bib116","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0155800","article-title":"Midkine increases diagnostic yield in AFP negative and NASH-related hepatocellular carcinoma","volume":"11","author":"Vongsuvanh","year":"2016","journal-title":"PLoS One"},{"key":"10.1016\/j.canlet.2026.218258_bib117","doi-asserted-by":"crossref","first-page":"87462","DOI":"10.18632\/oncotarget.13865","article-title":"Midkine is a serum and urinary biomarker for the detection and prognosis of non-small cell lung cancer","volume":"7","author":"Xia","year":"2016","journal-title":"Oncotarget"}],"container-title":["Cancer Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0304383526000212?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0304383526000212?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T14:55:25Z","timestamp":1778684125000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0304383526000212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":117,"alternative-id":["S0304383526000212"],"URL":"https:\/\/doi.org\/10.1016\/j.canlet.2026.218258","relation":{},"ISSN":["0304-3835"],"issn-type":[{"value":"0304-3835","type":"print"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target","name":"articletitle","label":"Article Title"},{"value":"Cancer Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.canlet.2026.218258","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"218258"}}