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Molecular Mechanisms and Therapies for Melanoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 October 2026 | Viewed by 14413

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Dr. Anna Piotrowska

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Department of Histology, Medical University of Gdansk, 1a Debinki, 80-211 Gdansk, Poland
Interests: melanoma; patient-derived melanoma models; adjuvant therapy in melanoma; microenvironment in melanoma; skin cancer; skin; UV; vitamin D and its derivatives; dermatoendocrinology; mitochondria; oxidative stress

Special Issue Information

Dear Colleagues,

Melanoma, representing only a minor percentage of all skin neoplasms, is responsible for the vast majority of deaths caused by cutaneous cancers. Moreover, the incidence of this aggressive malignancy has been dynamically increasing worldwide since 1975. Before 2011, advanced melanoma patients could expect a 5-year survival rate of 10%. Novel advanced therapies and their combinations, including immunotherapy with the immune checkpoint inhibitors CTLA-4 or PD-1, as well as targeted therapy with BRAF and MEK inhibitors, have become a critical breakthrough in the clinical landscape of melanoma treatment, as they resulted in an increase in the 5-year overall survival rate for metastatic melanoma to as much as 36%. Unfortunately, a substantial proportion of patients still either fail to respond to the therapy or will relapse over time, implying that melanoma remains a demanding clinical problem. Taking this into account, it seems necessary to continuously search for novel molecular targets and therapeutic solutions to overcome this fatal cancer. Advances in the field of molecular oncology and an increasingly precise understanding of the mechanisms and interactions within cancer nests have drawn attention to the critical role of the tumor microenvironment at all stages of tumorigenesis, establishing a new promising direction in cancer research, including melanoma.

This Special Issue provides insights into the molecular mechanisms of melanoma development, including the role of the tumor microenvironment, as well as recent advances in melanoma therapy, with a focus on novel potential therapeutic targets.

Dr. Anna Piotrowska
Guest Editor

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Keywords

melanoma
targeted therapy
BRAF/MEK inhibitors
immunotherapy
anti-PD-1 and anti-CTLA-4 immunotherapy
melanoma microenvironment
cancer-associated fibroblasts (CAFs)/melanoma-associated fibroblasts (MAFs)
MAPK (mitogen-activated protein kinase) signaling pathway

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Published Papers (4 papers)

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Research

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21 pages, 4383 KB

Open AccessArticle

Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy

by Laura Soumoy, Aline Genbauffe, Dorianne Sant’Angelo, Maude Everaert, Léa Mukeba-Harchies, Jean-Emmanuel Sarry, Anne-Emilie Declèves and Fabrice Journe

Int. J. Mol. Sci. 2025, 26(17), 8241; https://doi.org/10.3390/ijms26178241 - 25 Aug 2025

Cited by 6 | Viewed by 4048

Abstract

Targeted therapy with BRAFi has significantly improved outcomes for patients with BRAF-mutated metastatic melanoma. However, resistance mechanisms, particularly metabolic adaptations, such as increased glutaminolysis, present substantial clinical challenges. This study investigated the metabolic changes underlying BRAFi resistance in melanoma cells. Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. Our methodologies included cell culture, qPCR, polysome profiling, animal studies in nude mice, and analyses of patient samples to evaluate the therapeutic potential of targeting glutaminolysis. Our findings confirmed that melanoma cells, with resistance to targeted therapies, exhibit metabolic adaptations, including enhanced glutaminolysis, increased mitochondrial content, and elevated antioxidative capacities. We evaluated the efficacy of CB-839 and demonstrated its ability to reduce the proliferation of resistant melanoma cells both in vitro and in vivo. Mechanistic studies revealed that CB-839 suppressed ATP production and TCA cycle intermediates in resistant cells while inducing oxidative stress in sensitive cells, thereby inhibiting their proliferation. High glutaminase expression in primary patient tumor samples was associated with poor prognosis. We identified a metabolic signature in tumors from patients responsive or unresponsive to BRAFi prior to treatment, which could serve as a predictive factor for BRAFi response. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies for Melanoma)

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Review

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20 pages, 726 KB

Open AccessReview

The Diagnostic and Prognostic Role of Combined p16 and MTAP Immunohistochemistry in Melanocytic Tumors of Uncertain Malignant Potential: A Comprehensive Review and Clinical Practice Analysis

by Ludovica Pepe, Vincenzo Fiorentino, Cristina Pizzimenti, Maurizio Martini, Mariacarmela Santarpia, Antonina Fazio, Mario Vaccaro, Maria Lentini and Antonio Ieni

Int. J. Mol. Sci. 2026, 27(2), 971; https://doi.org/10.3390/ijms27020971 - 19 Jan 2026

Cited by 1 | Viewed by 1730

Abstract

Melanocytic Tumors of Uncertain Malignant Potential (MELTUMPs) remain among the most challenging entities in dermatopathology due to overlapping morphologic features and marked inter-observer variability. This comprehensive review critically assesses the diagnostic and potential prognostic significance of combining p16 and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) as a practical surrogate for genomic alterations involving the 9p21 (CDKN2A/MTAP) locus. We analyzed the molecular underpinnings of the CDKN2A/MTAP axis and systematically reviewed existing literature to define an integrated IHC strategy for ambiguous melanocytic lesions. The combined use of p16, a sensitive marker of CDKN2A inactivation, and MTAP, a highly specific marker for homozygous 9p21 deletion, was assessed for its diagnostic complementarity and potential clinical utility. p16 IHC demonstrates high sensitivity but limited specificity due to heterogeneous staining in borderline lesions. In contrast, MTAP loss exhibits near-absolute specificity for CDKN2A/MTAP co-deletion, albeit with lower sensitivity. Concordant loss of both markers strongly supports melanoma or high-risk melanocytoma, while MTAP retention may predict responsiveness to adjuvant interferon therapy. Combined p16/MTAP IHC provides a synergistic, biologically grounded approach that refines diagnostic accuracy in MELTUMPs. This dual-marker algorithm promotes a shift from purely morphology-based evaluation toward a reproducible, molecularly informed classification, improving both diagnostic confidence and patient management. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies for Melanoma)

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31 pages, 2698 KB

Open AccessReview

Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications

by Hubert Sikorski, Michał Aleksander Żmijewski and Anna Piotrowska

Int. J. Mol. Sci. 2025, 26(14), 6778; https://doi.org/10.3390/ijms26146778 - 15 Jul 2025

Cited by 23 | Viewed by 5604

Abstract

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies for Melanoma)

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28 pages, 4414 KB

Open AccessReview

Unravelling the Regulatory Roles of lncRNAs in Melanoma: From Mechanistic Insights to Target Selection

by Beatrice Moras and Claudia Sissi

Int. J. Mol. Sci. 2025, 26(5), 2126; https://doi.org/10.3390/ijms26052126 - 27 Feb 2025

Cited by 2 | Viewed by 2217

Abstract

Melanoma is the deadliest form of skin cancer, and its treatment poses significant challenges due to its aggressive nature and resistance to conventional therapies. Long non-coding RNAs (lncRNAs) represent a new frontier in the search for suitable targets to control melanoma progression and invasiveness. Indeed, lncRNAs exploit a wide range of regulatory functions along chromatin remodeling, gene transcription, post-transcription, transduction, and post-transduction to ultimately tune multiple cellular processes. The understanding of this intricate and flexible regulatory network orchestrated by lncRNAs in pathological conditions can strategically support the rational identification of promising targets, ultimately speeding up the setup of new therapeutics to integrate the currently available approaches. Here, the most recent findings on lncRNAs involved in melanoma will be analyzed. In particular, the functional links between their mechanisms of action and some frequently underestimated features, like their different subcellular localizations, will be highlighted. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies for Melanoma)

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