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Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt\/\u03b2-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial\u2013mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma.<\/jats:p>","DOI":"10.3390\/ijms26157419","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"7419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cancer Stem Cells in Melanoma: Drivers of Tumor Plasticity and Emerging Therapeutic Strategies"],"prefix":"10.3390","volume":"26","author":[{"given":"Adrian-Hora\u021biu","family":"Sab\u0103u","sequence":"first","affiliation":[{"name":"Doctoral School of Medicine and Pharmacy, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9603-6256","authenticated-orcid":false,"given":"Andreea-C\u0103t\u0103lina","family":"Tinca","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9016-5412","authenticated-orcid":false,"given":"Raluca","family":"Niculescu","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5985-2433","authenticated-orcid":false,"given":"Iuliu Gabriel","family":"Cocuz","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea Raluca","family":"Cozac-Sz\u00f6ke","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca Andreea","family":"Lazar","sequence":"additional","affiliation":[{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana Maria","family":"Chiorean","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7785-0121","authenticated-orcid":false,"given":"Corina Eugenia","family":"Budin","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pneumology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ovidiu Simion","family":"Cotoi","sequence":"additional","affiliation":[{"name":"Pathophysiology Department, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d of Targu Mures, 540142 Targu Mures, Romania"},{"name":"Pathology Department, Clinical County Hospital Mure\u0219, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lopes, J., Rodrigues, C.M.P., Gaspar, M.M., and Reis, C.P. 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