Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions.

Kayla T O'Toole; Brandon M Roan; Timothy M Hardman; Peyton P Phillips; Evan M VanBrocklin; Gennie L Parkman; Sheri L Holmen

doi:10.3390/ijms27042019

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Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions.

Kayla T O'Toole·Brandon M Roan·Timothy M Hardman·Peyton P Phillips·Evan M VanBrocklin·Gennie L Parkman·Sheri L Holmen

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Abstract

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-brain 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.

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Humans Melanoma Brain Neoplasms Animals Tumor Microenvironment Blood-Brain Barrier Immunotherapy BRAF NRAS PI3K/AKT brain metastases brain microenvironment immune checkpoint inhibitors melanoma preclinical models therapeutic resistance Journal Article Review

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Kayla T O'Toole, Brandon M Roan, Timothy M Hardman, Peyton P Phillips, Evan M VanBrocklin, Gennie L Parkman, Sheri L Holmen. 2026-02-20. Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions.. https://doi.org/10.3390/ijms27042019

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