{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:41:13Z","timestamp":1789684873009,"version":"4.0.1"},"reference-count":330,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Romanian Ministry of Education and Research NUCLEU","award":["PN 23.16.01.02"],"award-info":[{"award-number":["PN 23.16.01.02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Cutaneous melanoma (CM) is one of the most aggressive skin malignancies due to its rapid progression and high therapeutic resistance. Growing evidence demonstrates that the tumor microenvironment (TME)\u2014comprising diverse immune, stromal, vascular, and epidermal cell populations alongside various cytokines and growth factors, as well as extracellular matrix (ECM) components\u2014plays a crucial role in tumor heterogeneity, metastatic potential, and response to therapy. This review aims to synthesise current knowledge on the cellular and non-cellular constituents of the CM microenvironment and clarify their contributions to tumor progression, immune evasion, and treatment resistance. Materials and Methods: We conducted a narrative review of recent experimental, clinical, and translational studies investigating melanoma\u2013microenvironment interactions, integrating evidence from in vitro, in vivo, and human tissue analyses. Results: Melanoma exhibits marked intra-tumoral heterogeneity driven by genetic, epigenetic, and microenvironmental influences. Cancer-associated fibroblasts, adipocytes, endothelial cells, and keratinocytes are reprogrammed by melanoma cells to promote invasion, angiogenesis, and metastasis. Immune subsets play divergent roles: neutrophils, M2 macrophages, myeloid-derived suppressor cells, and tolerogenic dendritic cells foster immune suppression, while lymphocytes\u2014particularly CD8+ T cells, TFH cells, and B cells \u2014are associated with improved outcomes but often become dysfunctional. ECM remodeling, including collagen deposition, integrin signaling, and increased matrix stiffness, actively remodels the tissue to support tumor growth and immune evasion. Hypoxia-inducible factor (HIF)-mediated signaling drives cell dedifferentiation, angiogenesis, and metabolic changes that contribute to treatment resistance. Consequently, emerging therapeutic strategies are moving beyond targeting tumor cells alone to focus on modulating TME components, counteracting immunosuppression, hypoxia, metabolic reprogramming, and extracellular vesicle signaling. Conclusions: The TME profoundly modulates tumor behavior and therapeutic response. A deeper understanding of the reciprocal interactions between melanoma cells and their microenvironmental components may enable the development of more effective strategies for early detection, prognosis, and personalized therapies.<\/jats:p>","DOI":"10.3390\/medicina62040739","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T11:38:26Z","timestamp":1776080306000},"page":"739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Uncovering the Intricate and Heterogeneous Cellular Microenvironment of Cutaneous Melanoma"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5695-9208","authenticated-orcid":false,"given":"Dana Antonia","family":"\u021a\u0103poi","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology and Histology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2040-8671","authenticated-orcid":false,"given":"Ioana Maria","family":"Lambrescu","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology and Histology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u201cVictor Babe\u0219\u201d National Institute of Pathology, 050096 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4580-104X","authenticated-orcid":false,"given":"Catalin Gabriel","family":"Manole","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology and Histology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u201cVictor Babe\u0219\u201d National Institute of Pathology, 050096 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2582-3248","authenticated-orcid":false,"given":"Gisela","family":"Gaina","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology and Histology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u201cVictor Babe\u0219\u201d National Institute of Pathology, 050096 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Cristina","family":"Ceafalan","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology and Histology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u201cVictor Babe\u0219\u201d National Institute of Pathology, 050096 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1080\/15384047.2019.1640032","article-title":"Current state of melanoma diagnosis and treatment","volume":"20","author":"Davis","year":"2019","journal-title":"Cancer Biol. 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