Cutaneous Melanoma: Updating from Pathogenesis to Therapy

Dear Colleagues,

Cutaneous melanoma is rapidly emerging as a major public health threat, driven by rising incidence rates and surprisingly high mortality. Therefore, the need to unravel its complex causes and the molecular mechanisms sustaining its aggressiveness, as well as discovering those keen-specific biomarkers for early detection and monitoring, has never been more critical. Moreover, this scientific pursuit would be completed by completing and revising the current therapies or identifying novel therapeutic protocols.

The recent advances in melanoma research have enriched the perception and understanding of its pathogenesis, anticipating and blueprinting new diagnostic, prognostic, and therapeutic strategies. It was acknowledged that melanoma, the most aggressive skin cancer, features high metastatic potential and therapeutic resistance. The recurrent somatic mutations in key oncogenes and tumor suppressors that drive melanomagenesis (like BRAF, NRAS, NF1, CDKN2A, KIT, etc.) alter cellular signaling pathways like MAPK/ERK and/or MAPK. These, in fact, lead to increased cellular proliferation, cellular survival, and evasion of apoptosis. On the other hand, the epigenetic changes in melanoma like DNA methylation, histone modification, and regulation by non-coding RNAs are also involved in the development of melanoma and its progression by influencing the patterns of gene expressions and changing the cellular phenotypes. This contributes to melanoma heterogeneity and therapeutic resistance.

Supplementary, melanoma pathogenesis also consists of a tumor microenvironment made of immune cells, cancer-associated fibroblasts, endothelial cells, and other extracellular matrix components. The tumor microenvironment facilitates tumor growth, invasion, and immune evasion. Immune checkpoint molecules help melanoma cells to escape immune surveillance. On the other hand, the tumor-infiltrating lymphocytes gain value as prognostic and predictive biomarkers, with the levels of these lymphocytes being correlated with the outcomes. The single-cell RNA sequencing and spatial transcriptomics have enhanced our understanding of intratumoral heterogeneity and cell–cell interactions within the TME.

Moreover, tumor metabolism is another frontier in melanoma research, since it is well known that cells exhibit metabolic plasticity, enabling their mechanisms of adaptation to hostile microenvironments. Alterations in glycolysis, glutamine metabolism, fatty acid oxidation, or inhibitors of metabolic enzymes could represent new potential therapeutic targets. Nonetheless, the integration of artificial intelligence and machine learning into dermatologic imaging and genomic data interpretation further supports personalized therapeutic strategies.

Immunotherapy has transformed the melanoma treatment potential. Immune checkpoint inhibitors have demonstrated durable responses in a subset of patients. However, emerging strategies like personalized cancer vaccines targeting neoantigens, adoptive cell therapies using ex vivo expanded tumor-infiltrating lymphocytes, or engineered T cells or intratumoral therapies like oncolytic therapies which promote direct tumor lysis and immune activation show attractive melanoma management potential.

In conclusion, the evolving landscape of melanoma research emphasizes a comprehensive approach encompassing genomic, epigenomic, immunologic, and metabolic dimensions.

We encourage the submission of a wide spectrum of articles such as original research and reviews. Thus, we gladly invite fellow researchers and clinicians to contribute to this Special Issue focusing on the latest advances in understanding the pathogenesis and improving the diagnosis and treatment of cutaneous melanoma. The submission of papers addressing the complex molecular foundation of this disease, diagnostic approaches (including clinical, histopathological, immunohistochemical, molecular tests, and novel biomarkers), and monitoring and treatment options ranging from surgical techniques to the latest target therapies is welcome.

Dr. Catalin G. Manole
Guest Editor

Dr. Dana Antonia Țăpoi
Guest Editor Assistant

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• cutaneous melanoma
• pathogenesis
• surgery
• diagnosis
• biomarkers
• melanoma management