{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T17:01:29Z","timestamp":1789232489169,"version":"build-2803163510"},"reference-count":194,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["R01 CA121118"],"award-info":[{"award-number":["R01 CA121118"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melanoma, a highly aggressive and metastatic cancer, poses significant challenges due to its propensity to spread to distant organs, with brain metastasis representing a particularly devastating complication. This review synthesizes preclinical and clinical evidence on the molecular, cellular, and microenvironmental mechanisms driving melanoma metastasis, emphasizing mechanisms of blood\u2013brain barrier traversal, tumor-stroma co-option, and brain-specific genomic and transcriptional programs. We summarize advances in therapeutic strategies to combat melanoma brain metastasis including novel small molecules, immunotherapies, and combination approaches tailored for brain metastases. The review also highlights the immunological landscape of the brain, translational models, and multidisciplinary clinical management strategies. Finally, we identify critical research gaps, including the need for brain metastasis-specific clinical trials, AI-driven predictive models, and preventive strategies, to guide future efforts in improving outcomes for patients with melanoma brain metastasis.<\/jats:p>","DOI":"10.3390\/ijms27042019","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T13:08:23Z","timestamp":1771592903000},"page":"2019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-695X","authenticated-orcid":false,"given":"Kayla T.","family":"O\u2019Toole","sequence":"first","affiliation":[{"name":"Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Roan","sequence":"additional","affiliation":[{"name":"Jerry M. Wallace School of Osteopathic Medicine, Campbell University, Lillington, NC 27507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Hardman","sequence":"additional","affiliation":[{"name":"Jerry M. Wallace School of Osteopathic Medicine, Campbell University, Lillington, NC 27507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peyton P.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Jerry M. Wallace School of Osteopathic Medicine, Campbell University, Lillington, NC 27507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan M.","family":"VanBrocklin","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9432-4353","authenticated-orcid":false,"given":"Gennie L.","family":"Parkman","sequence":"additional","affiliation":[{"name":"Department of Zoology, Weber State University, Ogden, UT 84403, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6411-6032","authenticated-orcid":false,"given":"Sheri L.","family":"Holmen","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA"},{"name":"Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA"},{"name":"Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"ref_1","unstructured":"Sundararajan, S., Thida, A.M., Yadlapati, S., Mukkamalla, S.K.R., and Koya, S. (2025). Metastatic Melanoma. StatPearls, StatPearls Publishing LLC.. StatPearls Publishing Copyright \u00a9 2025."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e21522","DOI":"10.1200\/JCO.2024.42.16_suppl.e21522","article-title":"Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era","volume":"42","author":"Lee","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3390\/clinpract14010018","article-title":"A Narrative Review of Current Knowledge on Cutaneous Melanoma","volume":"14","author":"Caraban","year":"2024","journal-title":"Clin. Pract."},{"key":"ref_4","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2245269","DOI":"10.1001\/jamanetworkopen.2022.45269","article-title":"Melanoma Treatments and Mortality Rate Trends in the US, 1975 to 2019","volume":"5","author":"Kahlon","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.det.2025.03.008","article-title":"Pathology of Melanoma: New Concepts (2025 Update)","volume":"43","author":"Galambus","year":"2025","journal-title":"Dermatol. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrc.2016.37","article-title":"From melanocytes to melanomas","volume":"16","author":"Shain","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0046-8177(84)80310-X","article-title":"A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma","volume":"15","author":"Clark","year":"1984","journal-title":"Hum. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1056\/NEJMra052166","article-title":"Melanoma","volume":"355","author":"Miller","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.trecan.2015.07.009","article-title":"Surviving at a Distance: Organ-Specific Metastasis","volume":"1","author":"Obenauf","year":"2015","journal-title":"Trends Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.molonc.2013.02.009","article-title":"Rebuilding cancer metastasis in the mouse","volume":"7","author":"Saxena","year":"2013","journal-title":"Mol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1093\/neuonc\/not222","article-title":"Functional role of endothelial adhesion molecules in the early stages of brain metastasis","volume":"16","author":"Soto","year":"2014","journal-title":"Neuro-Oncology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1926190","DOI":"10.1080\/21688370.2021.1926190","article-title":"The blood-brain and gut-vascular barriers: From the perspective of claudins","volume":"9","author":"Scalise","year":"2021","journal-title":"Tissue Barriers"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1016\/j.jid.2017.08.029","article-title":"Lymphatic versus Hematogenous Melanoma Metastases: Support for Biological Heterogeneity without Clear Clinical Application","volume":"137","author":"Kasumova","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.20892\/j.issn.2095-3941.2025.0048","article-title":"Unraveling vascular mechanisms in melanoma: Roles of angiogenesis and vasculogenic mimicry in tumor progression and therapeutic resistance","volume":"22","author":"Raho","year":"2025","journal-title":"Cancer Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.ccr.2013.08.018","article-title":"A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma","volume":"24","author":"Caramel","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1111\/pcmr.12538","article-title":"Melanoma central nervous system metastases: Current approaches, challenges, and opportunities","volume":"29","author":"Cohen","year":"2016","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"115253","DOI":"10.1016\/j.ejca.2025.115253","article-title":"Survival improvements in patients with melanoma brain metastases and leptomeningeal disease in the modern era: Insights from a nationwide study (2015\u20132022)","volume":"217","author":"Pedersen","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.bcp.2017.12.019","article-title":"The biology and therapeutic management of melanoma brain metastases","volume":"153","author":"Ramello","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"vdaa140","DOI":"10.1093\/noajnl\/vdaa140","article-title":"An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study","volume":"2","author":"Amaral","year":"2020","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bonzano, E., Barruscotti, S., Chiellino, S., Montagna, B., Bonzano, C., Imarisio, I., Colombo, S., Guerrini, F., Saddi, J., and La Mattina, S. (2025). Current Treatment Paradigms for Advanced Melanoma with Brain Metastases. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202502.1395.v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"102083","DOI":"10.1016\/j.ctrv.2020.102083","article-title":"Melanoma brain metastases\u2014Interdisciplinary management recommendations 2020","volume":"89","author":"Gutzmer","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/S1470-2045(18)30139-6","article-title":"Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: A multicentre randomised phase 2 study","volume":"19","author":"Long","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nowacka, A., Fajkiel-Madajczyk, A., Ohla, J., Wo\u017aniak-D\u0105browska, K., Liss, S., Gryczka, K., Smuczy\u0144ski, W., Zi\u00f3\u0142kowska, E., Bo\u017ci\u0142ow, D., and \u015aniegocki, M. (2023). Current Treatment of Melanoma Brain Metastases. Cancers, 15.","DOI":"10.3390\/cancers15164088"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1056\/NEJMoa1805453","article-title":"Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain","volume":"379","author":"Tawbi","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ng, M.F., Simmons, J.L., and Boyle, G.M. (2022). Heterogeneity in Melanoma. Cancers, 14.","DOI":"10.3390\/cancers14123030"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s43556-024-00182-2","article-title":"Heterogeneity and molecular landscape of melanoma: Implications for targeted therapy","volume":"5","author":"Beigi","year":"2024","journal-title":"Mol. Biomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.celrep.2014.06.045","article-title":"Heterogeneous tumor subpopulations cooperate to drive invasion","volume":"8","author":"Chapman","year":"2014","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1056\/NEJMoa1502583","article-title":"The Genetic Evolution of Melanoma from Precursor Lesions","volume":"373","author":"Shain","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Balch, C.M., Urist, M.M., Karakousis, C.P., Smith, T.J., Temple, W.J., Drzewiecki, K., Jewell, W.R., Bartolucci, A.A., Mihm, M.C., and Barnhill, R. (1993). Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann. Surg., 218.","DOI":"10.1097\/00000658-199309000-00005"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/onc.2013.194","article-title":"Melanoma metastasis: New concepts and evolving paradigms","volume":"33","author":"Damsky","year":"2014","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Castellani, G., Buccarelli, M., Arasi, M.B., Rossi, S., Pisanu, M.E., Bellenghi, M., Lintas, C., and Tabolacci, C. (2023). BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers. Cancers, 15.","DOI":"10.3390\/cancers15164026"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1200\/JCO.2010.32.4327","article-title":"Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma","volume":"29","author":"Long","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1111\/ced.15113","article-title":"BRAF V600K vs. BRAF V600E: A comparison of clinical and dermoscopic characteristics and response to immunotherapies and targeted therapies","volume":"47","author":"Zengarini","year":"2022","journal-title":"Clin. Exp. Dermatol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nrc3760","article-title":"Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond","volume":"14","author":"Holderfield","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/311671a0","article-title":"A novel transforming gene in a human malignant melanoma cell line","volume":"311","author":"Padua","year":"1984","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1200\/JCO.2011.41.2452","article-title":"BRAF\/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma","volume":"30","author":"Colombino","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4014","DOI":"10.1002\/cncr.26724","article-title":"NRAS mutation status is an independent prognostic factor in metastatic melanoma","volume":"118","author":"Jakob","year":"2012","journal-title":"Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/exd.14489","article-title":"The role of PI3\u2032-lipid signalling in melanoma initiation, progression and maintenance","volume":"31","author":"Parkman","year":"2022","journal-title":"Exp. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5104","DOI":"10.1172\/JCI69619","article-title":"Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma","volume":"123","author":"Deuker","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/ng1634","article-title":"The melanocyte differentiation program predisposes to metastasis after neoplastic transformation","volume":"37","author":"Gupta","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.cell.2012.06.024","article-title":"A landscape of driver mutations in melanoma","volume":"150","author":"Hodis","year":"2012","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/ng.356","article-title":"Braf(V600E) cooperates with Pten loss to induce metastatic melanoma","volume":"41","author":"Dankort","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7002","DOI":"10.1158\/0008-5472.CAN-04-1399","article-title":"Deregulated Akt3 activity promotes development of malignant melanoma","volume":"64","author":"Stahl","year":"2004","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1200\/JCO.2005.07.168","article-title":"Prognostic significance of activated Akt expression in melanoma: A clinicopathologic study of 292 cases","volume":"23","author":"Dai","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7538","DOI":"10.1158\/1078-0432.CCR-09-1985","article-title":"Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma","volume":"15","author":"Davies","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.celrep.2015.09.057","article-title":"AKT1 Activation Promotes Development of Melanoma Metastases","volume":"13","author":"Cho","year":"2015","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1158\/1541-7786.MCR-18-1372","article-title":"AKT1(E17K) Activates Focal Adhesion Kinase and Promotes Melanoma Brain Metastasis","volume":"17","author":"Kircher","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1093\/neuonc\/noab159","article-title":"The PI3K\/Akt\/mTOR pathway as a preventive target in melanoma brain metastasis","volume":"24","author":"Tehranian","year":"2022","journal-title":"Neuro-Oncology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1158\/1535-7163.MCT-23-0474","article-title":"Genetic Silencing of AKT Induces Melanoma Cell Death via mTOR Suppression","volume":"23","author":"Parkman","year":"2024","journal-title":"Mol. Cancer Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1200\/jco.2010.28.15_suppl.3009","article-title":"First-in-class phase I trial of a selective Akt inhibitor, MK2206 (MK), evaluating alternate day (QOD) and once weekly (QW) doses in advanced cancer patients (pts) with evidence of target modulation and antitumor activity","volume":"28","author":"Yap","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1158\/1078-0432.CCR-11-2381","article-title":"The Clinical Effect of the Dual-Targeting Strategy Involving PI3K\/AKT\/mTOR and RAS\/MEK\/ERK Pathways in Patients with Advanced Cancer","volume":"18","author":"Shimizu","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1111\/febs.16021","article-title":"Epithelial-to-mesenchymal-like transition events in melanoma","volume":"289","author":"Pedri","year":"2022","journal-title":"Febs J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/ng0996-50","article-title":"Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocyte characteristics","volume":"14","author":"Tachibana","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1083\/jcb.142.3.827","article-title":"Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes","volume":"142","author":"Bertolotto","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1034\/j.1600-0749.2000.130203.x","article-title":"Cyclic AMP a key messenger in the regulation of skin pigmentation","volume":"13","author":"Ballotti","year":"2000","journal-title":"Pigment Cell Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"33042","DOI":"10.1074\/jbc.273.49.33042","article-title":"alpha-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome","volume":"273","author":"Price","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"14013","DOI":"10.1074\/jbc.C000113200","article-title":"Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a","volume":"275","author":"Takeda","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1101\/gad.14.2.158","article-title":"Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell formation, by the Wnt pathway","volume":"14","author":"Dorsky","year":"2000","journal-title":"Genes Dev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.ccr.2011.10.030","article-title":"\u03b2-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas","volume":"20","author":"Damsky","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1038\/onc.2012.229","article-title":"Beta-catenin inhibits melanocyte migration but induces melanoma metastasis","volume":"32","author":"Gallagher","year":"2013","journal-title":"Oncogene"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1158\/0008-5472.CAN-19-2373","article-title":"The EMT Transcription Factor ZEB2 Promotes Proliferation of Primary and Metastatic Melanoma While Suppressing an Invasive, Mesenchymal-Like Phenotype","volume":"80","author":"Vandamme","year":"2020","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1158\/0008-5472.CAN-10-2330","article-title":"Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis","volume":"71","author":"Casas","year":"2011","journal-title":"Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1002\/cncr.23086","article-title":"Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): A novel strategy for the treatment of melanoma and other malignancies","volume":"110","author":"Hamid","year":"2007","journal-title":"Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_66","first-page":"505","article-title":"Tremelimumab, a fully human monoclonal IgG2 antibody against CTLA4 for the potential treatment of cancer","volume":"9","author":"Tarhini","year":"2007","journal-title":"Curr. Opin. Mol. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","article-title":"Pembrolizumab versus Ipilimumab in Advanced Melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1056\/NEJMoa1412082","article-title":"Nivolumab in previously untreated melanoma without BRAF mutation","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.1016\/j.cell.2023.08.043","article-title":"The local microenvironment drives activation of neutrophils in human brain tumors","volume":"186","author":"Maas","year":"2023","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1158\/2326-6066.CIR-21-0870","article-title":"Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition","volume":"10","author":"Markson","year":"2022","journal-title":"Cancer Immunol. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.cell.2021.12.043","article-title":"Cellular architecture of human brain metastases","volume":"185","author":"Gonzalez","year":"2022","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Willsmore, Z.N., Harris, R.J., Crescioli, S., Hussein, K., Kakkassery, H., Thapa, D., Cheung, A., Chauhan, J., Bax, H.J., and Chenoweth, A. (2020). B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.622442"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Mazurkiewicz, J., Simiczyjew, A., Dratkiewicz, E., Zi\u0119tek, M., Matkowski, R., and Nowak, D. (2021). Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020529"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"282","DOI":"10.4049\/jimmunol.2000833","article-title":"Stromal Cell-Mediated Coordination of Immune Cell Recruitment, Retention, and Function in Brain-Adjacent Regions","volume":"206","author":"Ramaglia","year":"2021","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/s41419-023-06110-6","article-title":"Stromal cells in the tumor microenvironment: Accomplices of tumor progression?","volume":"14","author":"Zhao","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/s41388-024-02953-1","article-title":"YAP1 controls the N-cadherin-mediated tumor-stroma interaction in melanoma progression","volume":"43","author":"Xiao","year":"2024","journal-title":"Oncogene"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1182\/blood-2009-07-234757","article-title":"Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis","volume":"115","author":"Purushothaman","year":"2010","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3926","DOI":"10.1158\/0008-5472.CAN-17-3719","article-title":"Fibrin Stiffness Mediates Dormancy of Tumor-Repopulating Cells via a Cdc42-Driven Tet2 Epigenetic Program","volume":"78","author":"Liu","year":"2018","journal-title":"Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1158\/2159-8290.CD-20-0329","article-title":"Changes in Aged Fibroblast Lipid Metabolism Induce Age-Dependent Melanoma Cell Resistance to Targeted Therapy via the Fatty Acid Transporter FATP2","volume":"10","author":"Alicea","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1158\/2767-9764.CRC-23-0176","article-title":"Age-Related Increases in IGFBP2 Increase Melanoma Cell Invasion and Lipid Synthesis","volume":"4","author":"Alicea","year":"2024","journal-title":"Cancer Res. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/s43018-021-00272-y","article-title":"Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism","volume":"2","author":"Mazariegos","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Zeng, J., Lin, L., Ma, Y., Huang, W., Luo, Q., and Wen, J. (2025). Single-cell transcriptomics profiling reveals cellular origins and molecular drivers underlying melanoma brain metastasis. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0336502"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1016\/j.cell.2022.06.007","article-title":"Dissecting the treatment-naive ecosystem of human melanoma brain metastasis","volume":"185","author":"Biermann","year":"2022","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41698-023-00471-z","article-title":"Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases","volume":"7","author":"In","year":"2023","journal-title":"npj Precis. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.ccell.2021.01.011","article-title":"Melanoma models for the next generation of therapies","volume":"39","author":"Patton","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1158\/1541-7786.MCR-15-0189","article-title":"Tumor-Derived Cell Lines as Molecular Models of Cancer Pharmacogenomics","volume":"14","author":"Goodspeed","year":"2016","journal-title":"Mol. Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Mirabelli, P., Coppola, L., and Salvatore, M. (2019). Cancer Cell Lines Are Useful Model Systems for Medical Research. Cancers, 11.","DOI":"10.3390\/cancers11081098"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41392-023-01419-2","article-title":"Patient-derived xenograft models in cancer therapy: Technologies and applications","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_90","first-page":"57500","article-title":"A 3D Organotypic Melanoma Spheroid Skin Model","volume":"18","author":"Kulms","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12929-024-00997-9","article-title":"Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool","volume":"31","author":"Rodrigues","year":"2024","journal-title":"J. Biomed. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Mangani, S., Kremmydas, S., and Karamanos, N.K. (2025). Mimicking the Complexity of Solid Tumors: How Spheroids Could Advance Cancer Preclinical Transformative Approaches. Cancers, 17.","DOI":"10.3390\/cancers17071161"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5238","DOI":"10.1111\/febs.16778","article-title":"Recreating the extracellular matrix: Novel 3D cell culture platforms in cancer research","volume":"290","author":"Kyriakopoulou","year":"2023","journal-title":"Febs. J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"tkaf016","DOI":"10.1093\/burnst\/tkaf016","article-title":"Advances in engineered organoid models of skin for biomedical research","volume":"13","author":"Zeng","year":"2025","journal-title":"Burn. Trauma"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Abedellatif, S.E., Hosni, R., Waha, A., Gielen, G.H., Banat, M., Hamed, M., G\u00fcresir, E., Fr\u00f6hlich, A., Sirokay, J., and Wulf, A.L. (2024). Melanoma Brain Metastases Patient-Derived Organoids: An In Vitro Platform for Drug Screening. Pharmaceutics, 16.","DOI":"10.20944\/preprints202407.0598.v1"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1038\/s12276-024-01272-5","article-title":"Patient-derived tumor organoids: A new avenue for preclinical research and precision medicine in oncology","volume":"56","author":"Thorel","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s00262-025-04269-9","article-title":"Modeling anti-tumor immune responses using patient-derived melanoma organoids","volume":"75","author":"Kaminska","year":"2025","journal-title":"Cancer Immunol Immunother"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0002-9440(10)64719-0","article-title":"Human melanoma progression in skin reconstructs: Biological significance of bFGF","volume":"156","author":"Meier","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_99","first-page":"2937","article-title":"The three-dimensional human skin reconstruct model: A tool to study normal skin and melanoma progression","volume":"54","author":"Li","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1158\/0008-5472.CAN-20-0291","article-title":"Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines","volume":"80","author":"Valiente","year":"2020","journal-title":"Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Kircher, D.A., Silvis, M.R., Cho, J.H., and Holmen, S.L. (2016). Melanoma Brain Metastasis: Mechanisms, Models, and Medicine. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091468"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"101943","DOI":"10.1016\/j.xcrm.2025.101943","article-title":"Combined inhibition of focal adhesion kinase and RAF\/MEK elicits synergistic inhibition of melanoma growth and reduces metastases","volume":"6","author":"Almazan","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/neuonc\/noae219","article-title":"The immune landscape in brain metastasis","volume":"27","author":"Schreurs","year":"2025","journal-title":"Neuro-Oncology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1038\/s41593-019-0532-y","article-title":"Mapping microglia states in the human brain through the integration of high-dimensional techniques","volume":"22","author":"Sankowski","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1016\/j.celrep.2016.10.052","article-title":"Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies","volume":"17","author":"Bowman","year":"2016","journal-title":"Cell Rep."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"101178","DOI":"10.1016\/j.isci.2020.101178","article-title":"Cellular and Molecular Changes of Brain Metastases-Associated Myeloid Cells during Disease Progression and Therapeutic Response","volume":"23","author":"Schulz","year":"2020","journal-title":"iScience"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.neo.2021.09.001","article-title":"In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM\/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer","volume":"23","author":"Zhang","year":"2021","journal-title":"Neoplasia"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2958","DOI":"10.2353\/ajpath.2010.090838","article-title":"Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis","volume":"176","author":"Lorger","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/s43018-021-00254-0","article-title":"Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis","volume":"2","author":"Klemm","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.cell.2020.04.055","article-title":"Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes","volume":"181","author":"Friebel","year":"2020","journal-title":"Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.cell.2020.05.007","article-title":"Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells","volume":"181","author":"Klemm","year":"2020","journal-title":"Cell"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.molmed.2022.08.006","article-title":"Microglia-T cell conversations in brain cancer progression","volume":"28","author":"Mirzaei","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1038\/s41556-023-01273-y","article-title":"Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis","volume":"25","author":"Evans","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s43018-023-00566-3","article-title":"Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation","volume":"4","author":"Wischnewski","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Li, T., Sun, S., Li, Y., Zhang, Y., and Wei, L. (2024). Immunotherapy revolutionizing brain metastatic cancer treatment: Personalized strategies for transformative outcomes. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1418580"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/s41573-018-0007-y","article-title":"Approaches to treat immune hot, altered and cold tumours with combination immunotherapies","volume":"18","author":"Galon","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1124\/jpet.122.001571","article-title":"Agent-Based Modelling Reveals the Role of the Tumor Microenvironment on the Short-Term Success of Combination Temozolomide\/Immune Checkpoint Blockade to Treat Glioblastoma","volume":"387","author":"Surendran","year":"2023","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4109","DOI":"10.1158\/1078-0432.CCR-21-1694","article-title":"Single-Cell Characterization of the Immune Microenvironment of Melanoma Brain and Leptomeningeal Metastases","volume":"27","author":"Smalley","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1056\/NEJMoa2109970","article-title":"Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma","volume":"386","author":"Tawbi","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.jtho.2023.04.021","article-title":"Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1","volume":"18","author":"Reck","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00432-013-1553-7","article-title":"Predictive factors for the development of brain metastases in patients with malignant melanoma: A study by the Anatolian society of medical oncology","volume":"140","author":"Gumusay","year":"2014","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.canrad.2014.11.001","article-title":"[Epidemiology of brain metastases]","volume":"19","author":"Taillibert","year":"2015","journal-title":"Cancer Radiother."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.1158\/0008-5472.CAN-08-4347","article-title":"Brain metastasis: Opportunities in basic and translational research","volume":"69","author":"Maher","year":"2009","journal-title":"Cancer Res."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Cioffi, G., Ascha, M.S., Waite, K.A., Dmukauskas, M., Wang, X., Royce, T.J., Calip, G.S., Waxweiler, T., Rusthoven, C.G., and Kavanagh, B.D. (2024). Sex Differences in Odds of Brain Metastasis and Outcomes by Brain Metastasis Status after Advanced Melanoma Diagnosis. Cancers, 16.","DOI":"10.3390\/cancers16091771"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.3390\/ijms14011383","article-title":"Role of the blood-brain barrier in the formation of brain metastases","volume":"14","author":"Wilhelm","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nm.2072","article-title":"Real-time imaging reveals the single steps of brain metastasis formation","volume":"16","author":"Kienast","year":"2010","journal-title":"Nat. Med."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Anchan, A., Kalogirou-Baldwin, P., Johnson, R., Kho, D.T., Joseph, W., Hucklesby, J., Finlay, G.J., O\u2019Carroll, S.J., Angel, C.E., and Graham, E.S. (2019). Real-Time Measurement of Melanoma Cell-Mediated Human Brain Endothelial Barrier Disruption Using Electric Cell-Substrate Impedance Sensing Technology. Biosensors, 9.","DOI":"10.3390\/bios9020056"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Anchan, A., Martin, O., Hucklesby, J.J.W., Finlay, G., Johnson, R.H., Robilliard, L.D., O\u2019Carroll, S.J., Angel, C.E., and Graham, E.S. (2020). Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218193"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s10585-008-9193-z","article-title":"Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization","volume":"25","author":"Fitzgerald","year":"2008","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s13277-015-4242-0","article-title":"The role of astrocytes in the progression of brain cancer: Complicating the picture of the tumor microenvironment","volume":"37","author":"Placone","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"e154804","DOI":"10.1172\/jci.insight.154804","article-title":"MCP-1\/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression","volume":"7","author":"Pozzi","year":"2022","journal-title":"JCI Insight"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature15376","article-title":"Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth","volume":"527","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ccell.2025.01.008","article-title":"Microglial reprogramming enhances antitumor immunity and immunotherapy response in melanoma brain metastases","volume":"43","author":"Castillo","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.18632\/oncotarget.27686","article-title":"Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases","volume":"11","author":"In","year":"2020","journal-title":"Oncotarget"},{"key":"ref_135","unstructured":"(2025, December 19). NCCN Clinical Practice Guidelines In Oncology: Melanoma: Cutaneous. 2026, Version 1.2026. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/cutaneous_melanoma.pdf."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1002\/cncr.25634","article-title":"Prognostic factors for survival in melanoma patients with brain metastases","volume":"117","author":"Davies","year":"2011","journal-title":"Cancer"},{"key":"ref_137","unstructured":"Lekkala, M.R., and Mullangi, S. (2025). Malignant Melanoma Metastatic to the Central Nervous System. StatPearls, StatPearls Publishing LLC.. StatPearls Publishing Copyright \u00a9 2025."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1002\/1878-0261.12712","article-title":"Role of radiation oncology in modern multidisciplinary cancer treatment","volume":"14","author":"Valentini","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1093\/neuonc\/noad260","article-title":"Novel radiotherapeutic strategies in the management of brain metastases: Challenging the dogma","volume":"26","author":"Palmer","year":"2024","journal-title":"Neuro-Oncology"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Harrison, R.A., Tang, M., Shih, K.K., Khan, M., Pham, L., De Moraes, A.R., O\u2019Brien, B.J., Bassett, R., and Bruera, E. (2024). Characterization of patients with brain metastases referred to palliative care. BMC Palliat. Care, 23.","DOI":"10.1186\/s12904-023-01320-3"},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Wu, A., Col\u00f3n, G.R., and Lim, M. (2022). Quality of Life and Role of Palliative and Supportive Care for Patients With Brain Metastases and Caregivers: A Review. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.806344"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Kami\u0144ska, P., Buszka, K., Zabel, M., Nowicki, M., Alix-Panabi\u00e8res, C., and Budna-Tukan, J. (2021). Liquid Biopsy in Melanoma: Significance in Diagnostics, Prediction and Treatment Monitoring. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22189714"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"15330338221100355","DOI":"10.1177\/15330338221100355","article-title":"Emerging Technologies for the Detection of Cancer Micrometastasis","volume":"21","author":"Mao","year":"2022","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Ricciardi, E., Giordani, E., Ziccheddu, G., Falcone, I., Giacomini, P., Fanciulli, M., Russillo, M., Cerro, M., Ciliberto, G., and Morrone, A. (2023). Metastatic Melanoma: Liquid Biopsy as a New Precision Medicine Approach. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24044014"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Cherukuri, S.P., Kaur, A., Goyal, B., Kukunoor, H.R., Sahito, A.F., Sachdeva, P., Yerrapragada, G., Elangovan, P., Shariff, M.N., and Natarajan, T. (2025). Artificial Intelligence-Enhanced Liquid Biopsy and Radiomics in Early-Stage Lung Cancer Detection: A Precision Oncology Paradigm. Cancers, 17.","DOI":"10.3390\/cancers17193165"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/ird3.70027","article-title":"AI-Enhanced Predictive Imaging in Precision Medicine: Advancing Diagnostic Accuracy and Personalized Treatment","volume":"3","author":"Rajendran","year":"2025","journal-title":"iRADIOLOGY"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"267","DOI":"10.2478\/raon-2022-0032","article-title":"Radiation therapy for melanoma brain metastases: A systematic review","volume":"56","author":"Thompson","year":"2022","journal-title":"Radiol. Oncol."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Caruso, G., Garcia Moreira, C.G., Iaboni, E., Tripodo, M., Ferrarotto, R., Abbritti, R.V., Conte, L., and Caffo, M. (2025). Tumor Microenvironment in Melanoma Brain Metastasis: A New Potential Target?. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115018"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/S1470-2045(24)00735-6","article-title":"Ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases (ABC): 7-year follow-up of a multicentre, open-label, randomised, phase 2 study","volume":"26","author":"Long","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1200\/JCO.21.02314","article-title":"Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline","volume":"40","author":"Vogelbaum","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/cncr.30946","article-title":"Improved survival of patients with melanoma brain metastases in the era of targeted BRAF and immune checkpoint therapies","volume":"124","author":"Sloot","year":"2018","journal-title":"Cancer"},{"key":"ref_152","unstructured":"Hall, W.A., and Das, J.M. (2025). Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiotherapy (SBRT). StatPearls, StatPearls Publishing LLC.. StatPearls Publishing Copyright \u00a9 2025."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"8870","DOI":"10.1200\/JCO.2005.01.8747","article-title":"Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: An Eastern Cooperative Oncology Group study (E 6397)","volume":"23","author":"Manon","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1200\/JCO.2004.11.044","article-title":"Temozolomide for the treatment of brain metastases associated with metastatic melanoma: A phase II study","volume":"22","author":"Agarwala","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1016\/0959-8049(94)00297-I","article-title":"A phase II study of the sequential administration of dacarbazine and fotemustine in the treatment of cerebral metastases from malignant melanoma","volume":"30","author":"Chang","year":"1994","journal-title":"Eur. J. Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1186\/s13244-025-02125-z","article-title":"Assessing brain metastasis response to immunotherapy: A pictorial review of atypical responses and intracranial adverse events","volume":"16","author":"Amseian","year":"2025","journal-title":"Insights Imaging"},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Pikis, S., Mantziaris, G., Sheehan, K., Sheehan, D., and Sheehan, J.P. (2025). Hypo-Fractionated Stereotactic Radiosurgery for the Management of Brain Metastases. Cancers, 17.","DOI":"10.3390\/cancers17183026"},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Ono, T., and Nemoto, K. (2022). Re-Whole Brain Radiotherapy May Be One of the Treatment Choices for Symptomatic Brain Metastases Patients. Cancers, 14.","DOI":"10.3390\/cancers14215293"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"18","DOI":"10.25259\/SNI_913_2024","article-title":"Stereotactic radiosurgery versus whole-brain radiotherapy for intracranial metastases: A systematic review and meta-analysis","volume":"16","author":"Alrasheed","year":"2025","journal-title":"Surg. Neurol. Int."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.ijrobp.2009.05.001","article-title":"Dose escalation of whole-brain radiotherapy for brain metastases from melanoma","volume":"77","author":"Rades","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"401","DOI":"10.2217\/cns.14.40","article-title":"Whole-brain radiotherapy in patients with brain metastases from melanoma","volume":"3","author":"Beal","year":"2014","journal-title":"CNS Oncol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/S1470-2045(12)70431-X","article-title":"Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): A multicentre, open-label, phase 2 trial","volume":"13","author":"Long","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"115514","DOI":"10.1016\/j.ejca.2025.115514","article-title":"Efficacy of encorafenib plus binimetinib in patients with BRAF-mutated melanoma brain metastases: Results from the Dutch Melanoma Treatment Registry","volume":"223","author":"Bloem","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/cncr.32547","article-title":"Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series","volume":"126","author":"Holbrook","year":"2020","journal-title":"Cancer"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1093\/neuonc\/noae116","article-title":"Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN\/GEM1802 phase II study)","volume":"26","author":"Arance","year":"2024","journal-title":"Neuro-Oncology"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"5310","DOI":"10.1158\/1078-0432.CCR-20-1764","article-title":"A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor-Positive Breast Cancer","volume":"26","author":"Tolaney","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","article-title":"The blood-brain barrier: Bottleneck in brain drug development","volume":"2","author":"Pardridge","year":"2005","journal-title":"NeuroRx"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1056\/NEJMoa1611299","article-title":"Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy","volume":"375","author":"Eggermont","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1056\/NEJMoa2211437","article-title":"Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma","volume":"388","author":"Patel","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/pcmr.12945","article-title":"Connexins in melanoma: Potential role of Cx46 in its aggressiveness","volume":"34","author":"Orellana","year":"2021","journal-title":"Pigment Cell Melanoma Res"},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Soltantoyeh, T., Akbari, B., Karimi, A., Mahmoodi Chalbatani, G., Ghahri-Saremi, N., Hadjati, J., Hamblin, M.R., and Mirzaei, H.R. (2021). Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead. Cells, 10.","DOI":"10.3390\/cells10061450"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/2051-1426-2-25","article-title":"Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells","volume":"2","author":"Beard","year":"2014","journal-title":"J. Immunother. Cancer"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1111\/exd.13678","article-title":"The siRNA-mediated downregulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-T-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma","volume":"27","author":"Simon","year":"2018","journal-title":"Exp. Dermatol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"16024","DOI":"10.1038\/mto.2016.24","article-title":"Immunological quality and performance of tumor vessel-targeting CAR-T cells prepared by mRNA-EP for clinical research","volume":"3","author":"Inoo","year":"2016","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"7622","DOI":"10.7150\/thno.43991","article-title":"Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors","volume":"10","author":"Yang","year":"2020","journal-title":"Theranostics"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nrd4663","article-title":"Oncolytic viruses: A new class of immunotherapy drugs","volume":"14","author":"Kaufman","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1200\/JCO.2014.58.3377","article-title":"Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma","volume":"33","author":"Andtbacka","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Geletneky, K., Huesing, J., Rommelaere, J., Schlehofer, J.R., Leuchs, B., Dahm, M., Krebs, O., von Knebel Doeberitz, M., Huber, B., and Hajda, J. (2012). Phase I\/IIa study of intratumoral\/intracerebral or intravenous\/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-99"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"105295","DOI":"10.1016\/j.phrs.2020.105295","article-title":"Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux","volume":"163","author":"Xia","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10585-023-10202-0","article-title":"Repurposing fluphenazine to suppress melanoma brain, lung and bone metastasis by inducing G0\/G1 cell cycle arrest and apoptosis and disrupting autophagic flux","volume":"40","author":"Xi","year":"2023","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1158\/2159-8290.CD-24-0027","article-title":"Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers","volume":"14","author":"Jiang","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41586-024-07205-6","article-title":"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy","volume":"629","author":"Holderfield","year":"2024","journal-title":"Nature"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S1470-2045(13)70024-X","article-title":"MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: A non-randomised, open-label phase 2 study","volume":"14","author":"Ascierto","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1038\/s41591-025-03763-y","article-title":"Defactinib with avutometinib in patients with solid tumors: The phase 1 FRAME trial","volume":"31","author":"Banerjee","year":"2025","journal-title":"Nat. Med."},{"key":"ref_185","unstructured":"Colman, H., and Holmen, S.L. (2025, December 26). Defactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases from Cutaneous Melanoma (DETERMINE), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06194929?cond=melanoma&intr=defactinib&rank=1."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1158\/2159-8290.CD-18-1489","article-title":"Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases","volume":"9","author":"Fischer","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Li, M., Zhang, Y., Yu, D., Yu, Y., and Ma, W. (2025). Immunotherapy biomarkers in brain metastases: Insights into tumor microenvironment dynamics. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1600261"},{"key":"ref_188","doi-asserted-by":"crossref","unstructured":"Evangelou, K., Zemperligkos, P., Politis, A., Lani, E., Gutierrez-Valencia, E., Kotsantis, I., Velonakis, G., Boviatsis, E., Stavrinou, L.C., and Kalyvas, A. (2025). Diagnostic, Therapeutic, and Prognostic Applications of Artificial Intelligence (AI) in the Clinical Management of Brain Metastases (BMs). Brain Sci., 15.","DOI":"10.3390\/brainsci15070730"},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Benbenishty, A., Gadrich, M., Cottarelli, A., Lubart, A., Kain, D., Amer, M., Shaashua, L., Glasner, A., Erez, N., and Agalliu, D. (2019). Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. PLoS Biol., 17.","DOI":"10.1101\/533927"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"169","DOI":"10.14336\/AD.2023.0514","article-title":"The Role of Microglia in Brain Metastases: Mechanisms and Strategies","volume":"15","author":"Feng","year":"2024","journal-title":"Aging Dis."},{"key":"ref_191","doi-asserted-by":"crossref","unstructured":"Fenouille, N., Tichet, M., Dufies, M., Pottier, A., Mogha, A., Soo, J.K., Rocchi, S., Mallavialle, A., Galibert, M.D., and Khammari, A. (2012). The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040378"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S1470-2045(17)30429-1","article-title":"Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): A multicentre, multicohort, open-label, phase 2 trial","volume":"18","author":"Davies","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"393","DOI":"10.14694\/EdBook_AM.2013.33.393","article-title":"Multidisciplinary approach to brain metastasis from melanoma: The emerging role of systemic therapies","volume":"33","author":"Long","year":"2013","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"TPS3152","DOI":"10.1200\/JCO.2021.39.15_suppl.TPS3152","article-title":"Trial in progress: Phase 1a\/b study of PF-07284890 (brain-penetrant BRAF inhibitor) with\/without binimetinib in patients with BRAF V600-mutant solid tumors","volume":"39","author":"Subbiah","year":"2021","journal-title":"J. Clin. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:21:48Z","timestamp":1771935708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,20]]},"references-count":194,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27042019"],"URL":"https:\/\/doi.org\/10.3390\/ijms27042019","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,20]]}}}