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mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular...
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mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 March 2026) | Viewed by 16604

Special Issue Editors

Dr. Stefano Zoroddu

E-Mail Website
Guest Editor
Department of Biomedical Sciences, School of Medicine, University of Sassari, 07100 Sassari, Italy
Interests: oxidative stress biomarkers; lipid peroxidation (MDA, TMAO, MPO, IMA, PSH, etc.); redox biology; cancer; metabolomics; inflammation and immune response; bioanalytical methods
Prof. Dr. Luigi M. Bagella

E-Mail Website
Guest Editor
1. Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy
2. Sbarro Institute for Cancer Research and Molecular Medicine, Centre for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
Interests: cancer epigenetics; rhabdomyosarcoma; EZH2; SCLC; MYC; small molecules; nanoparticles; cytotoxicity; cell proliferation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

mRNA-based technologies are rapidly transforming melanoma research by enabling precise modulation of cellular pathways and antitumor immune responses. This Special Issue focuses on the mechanistic foundations and cellular impacts of mRNA vaccines and mRNA-based therapeutics within the context of melanoma biology. We welcome the submission of studies exploring innovative mRNA design, delivery systems, intracellular trafficking, translation efficiency, and the molecular mechanisms by which mRNA constructs shape innate and adaptive immune activation. Research examining tumor–immune cell interactions, antigen presentation, and signaling pathways influenced by mRNA-based interventions is particularly encouraged. By bringing together cutting-edge insights in RNA biology, immunology, and melanoma cell research, this Special Issue aims to advance our understanding of how mRNA technologies can be harnessed to reveal new molecular vulnerabilities and improve future therapeutic strategies. We look forward to receiving your valuable contributions.

Dr. Stefano Zoroddu
Prof. Dr. Luigi M. Bagella
Guest Editors

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Keywords

  • mRNA vaccines
  • melanoma
  • tumor immunology
  • mRNA vaccine designs
  • delivery systems

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Published Papers (6 papers)

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Research

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16 pages, 836 KB  
Article
mRNA Multipeptide-HLA Class II Immunotherapy for Melanoma
by Apostolos P. Georgopoulos, Lisa M. James and Matthew Sanders
Cells 2025, 14(18), 1430; https://doi.org/10.3390/cells14181430 - 12 Sep 2025
Cited by 3 | Viewed by 1556
Abstract
Human Leukocyte Antigen (HLA) Class II (HLA-II) molecules bind peptides of phagocytosed non-self proteins and present them on the cell surface to circulating CD4+ T lymphocytes. A successful binding of the presented peptide with the T cell receptor (TCR) activates the CD4+ T [...] Read more.
Human Leukocyte Antigen (HLA) Class II (HLA-II) molecules bind peptides of phagocytosed non-self proteins and present them on the cell surface to circulating CD4+ T lymphocytes. A successful binding of the presented peptide with the T cell receptor (TCR) activates the CD4+ T cell, leading to the production of antibodies against the peptide (and the protein of its origin) by the B cell and augmentation of the cytotoxic and memory functions of CD8+ T cells. The first and essential step in this process is the successful formation of a stable peptide-HLA-II complex (pHLA-II), which is achieved when the peptide binds with high affinity to the HLA-II molecule. Such highly antigenic non-self peptides occur in melanoma-associated proteins and could be used as antitumor agents when bound to a matching HLA-II molecule. The objective of this study was to identify such peptides from 15 melanoma-associated proteins. We determined in silico the predicted binding affinity (IC50) of all pHLA-II pairs between 192 common HLA-II molecules and all possible linear 15-amino acid (15-mer) peptides (epitopes) of 15 known melanoma-associated antigens (N = 3466 epitopes) for a total of 192 × 3466 = 665,472 determinations. From this set, we identified epitopes with strong antigenicity (predicted best binding affinity [PBBA] IC50 < 50 nM). Of a total of 665,472 pHLA-II tested, 5941 (0.89%) showed strong PBBA, stemming from 117 HLA-II alleles and 679 distinct epitopes. This set of 5941 pHLA-II pairs with predicted high antigenicity possesses the requisite information for devising multipeptide vaccines with those epitopes alone or in combination with the corresponding HLA-II molecules. The results obtained have a major implication for cancer therapy, namely that the administration of subsets of the 679 high antigenicity epitopes above, alone or in combination with their associated HLA-II molecules, would be successful in engaging CD4+ T helper lymphocytes to augment the cytotoxic action and memory of CD8+ T lymphocytes and induce the production of antitumor antibodies by B cells. This therapy would be effective in other solid tumors (in addition to melanoma) and would be enhanced by concomitant immunotherapy with immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
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Review

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17 pages, 835 KB  
Review
mRNA and Peptide Vaccines in Melanoma—Current Landscape and Future Direction
by Jiaxing Jason Qin, Yang Wang and Shahneen Sandhu
Cells 2026, 15(4), 344; https://doi.org/10.3390/cells15040344 - 13 Feb 2026
Viewed by 1192
Abstract
Immune checkpoint inhibitors have transformed the treatment landscape for advanced melanoma in the past 15 years, delivering unprecedented and durable survival benefits. This success has propelled the development of complementary immune-directed therapies, including cancer vaccines. Among these, synthetic long peptide (SLP) and mRNA [...] Read more.
Immune checkpoint inhibitors have transformed the treatment landscape for advanced melanoma in the past 15 years, delivering unprecedented and durable survival benefits. This success has propelled the development of complementary immune-directed therapies, including cancer vaccines. Among these, synthetic long peptide (SLP) and mRNA vaccine platforms have emerged as highly promising. Advances in next-generation sequencing technology, alongside computational neoantigen algorithm predictions, have enabled patient-specific neoantigen identification to improve vaccine immunogenicity and enhance therapeutic efficacy. Off-the-shelf and personalised SLP and mRNA vaccines have demonstrated the ability to induce robust antigen-specific T-cell responses and modulate the tumour microenvironment. Mechanistically, cancer vaccines synergise with immune checkpoint inhibition. This review outlines the current clinical development of mRNA and peptide vaccines in melanoma, highlighting the significant promise to synergise with immune checkpoint inhibition to enhance efficacy without adding to the systemic toxicity profile. The neoadjuvant setting, characterised by intact tumour antigens and draining lymphatic architecture, offers a compelling biological context for leveraging cancer vaccines for enhanced immune priming and response assessment. Collectively, the rapid advances in technology and emerging clinical data position cancer vaccines as a promising therapy capable of improving immunotherapy in Stage III and IV melanoma. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
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18 pages, 701 KB  
Review
mRNA Vaccines in Melanoma Immunotherapy—A Narrative Review
by Paulina Plewa, Maciej Ćmil, Filip Lewandowski, Agata Poniewierska-Baran and Andrzej Pawlik
Cells 2026, 15(3), 298; https://doi.org/10.3390/cells15030298 - 5 Feb 2026
Viewed by 1270
Abstract
Melanoma is one of the most aggressive forms of cancer and the leading cause of death related to skin disease. Recent years have seen a significant increase in the number of cases of this type of cancer, underscoring the need to develop effective [...] Read more.
Melanoma is one of the most aggressive forms of cancer and the leading cause of death related to skin disease. Recent years have seen a significant increase in the number of cases of this type of cancer, underscoring the need to develop effective therapeutic strategies to control it. One of the most promising research directions in this field is anticancer immunotherapy, particularly the use of vaccines aimed at enhancing the body’s cellular immunity. Among the modern methods of this type, mRNA-based vaccines are prominent, gaining increasing importance as a potential tool in cancer therapy. Their main advantages include a relatively rapid and flexible production process, low production costs, and the ability to induce both humoral and cellular immune responses. Despite their numerous advantages, therapeutic mRNA vaccines also pose a number of scientific and technological challenges. These primarily concern the stability of mRNA molecules and their effective delivery to target cells. In this context, delivery systems such as lipid nanoparticles (LNPs) play a key role, protecting mRNA from degradation and facilitating its transport into the cell cytoplasm. Alternatively, systems based on biodegradable polymers are also being developed, which can provide controlled mRNA release and additional biocompatibility. However, before therapeutic mRNA vaccines become a routine component of cancer therapy, extensive clinical trials and a thorough understanding of their mechanisms of action are necessary. This paper provides an overview of the current knowledge regarding the structure and delivery methods of therapeutic mRNA vaccines, with a particular emphasis on their use in melanoma therapy. The results of clinical trials to date are also presented and the challenges associated with implementing this form of therapy in medical practice are discussed. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
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25 pages, 351 KB  
Review
Advances in mRNA-Based Melanoma Vaccines: A Narrative Review of Lipid Nanoparticle and Dendritic Cell Delivery Platforms
by Connor K. Sisk, Laci M. Turner, Shafkat Meraj and Nabiha Yusuf
Cells 2026, 15(2), 99; https://doi.org/10.3390/cells15020099 - 6 Jan 2026
Cited by 1 | Viewed by 1616
Abstract
Melanoma remains one of the deadliest cutaneous malignancies worldwide, and despite advances in systemic therapy, recurrence and treatment resistance remain frequent challenges. Following the success of COVID-19 mRNA vaccines, mRNA-based cancer vaccines targeting melanoma antigens have emerged as a promising therapeutic direction. This [...] Read more.
Melanoma remains one of the deadliest cutaneous malignancies worldwide, and despite advances in systemic therapy, recurrence and treatment resistance remain frequent challenges. Following the success of COVID-19 mRNA vaccines, mRNA-based cancer vaccines targeting melanoma antigens have emerged as a promising therapeutic direction. This review summarizes current evidence on mRNA melanoma vaccines, focusing on two leading delivery platforms: lipid nanoparticles (LNPs) and dendritic cell (DC) vaccines. A comprehensive search of MEDLINE, Embase, and Scopus from 2015 to 2025 identified clinical trials, preclinical studies, and review articles evaluating mRNA vaccine constructs and delivery strategies. Completed clinical studies demonstrate that personalized LNP-formulated mRNA vaccines can enhance neoantigen-specific T-cell responses and improve recurrence-free survival, particularly when combined with immune checkpoint inhibitors. DC-based mRNA vaccines also show potent immunogenicity, with stronger responses observed when DC maturation is optimized. Ongoing trials continue to investigate next-generation LNP formulations, DC priming strategies, and personalized neoantigen approaches. Overall, current evidence indicates that both LNP and DC platforms can augment antitumor immunity by broadening T-cell responses and enhancing checkpoint inhibition. Continued refinement of delivery vehicles, neoantigen selection, and scalable manufacturing processes will be essential to realizing the full clinical potential of mRNA vaccines in melanoma. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
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21 pages, 1616 KB  
Review
The Evolution, Current Landscape, and Future Prospects of Oncolytic Virotherapy in Melanoma: Talimogene Laherparepvec and Beyond
by John Smestad, John Rieth, Douglas Laux and Mohammed Milhem
Cells 2025, 14(20), 1620; https://doi.org/10.3390/cells14201620 - 17 Oct 2025
Cited by 1 | Viewed by 2612
Abstract
Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses [...] Read more.
Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses and then the development of sophisticated Herpes simplex virus 1 (HSV-1) variant constructs such as talimogene laherparepvec (T-VEC) and vusolimogene oderparepvec (Replimune-1, RP1), which incorporate deletions of viral genes and expression of human or synthetic transgenes to promote tumor selectivity, dendritic cell recruitment, antigen presentation, and stimulation of systemic anti-tumor immune responses. We review the status of clinical trials of oncolytic viruses in melanoma, highlight regulatory challenges, and describe important concepts and key remaining questions within the field. While T-VEC remains the only Food and Drug Administration (FDA)-approved oncolytic virus for melanoma treatment, ongoing research focusing on next-generation viral constructs and combination strategies aims to further improve clinical outcomes and expand the applicability of oncolytic virus therapy in melanoma. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
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17 pages, 1030 KB  
Review
Next-Generation mRNA Vaccines in Melanoma: Advances in Delivery and Combination Strategies
by Stefano Zoroddu and Luigi Bagella
Cells 2025, 14(18), 1476; https://doi.org/10.3390/cells14181476 - 22 Sep 2025
Cited by 8 | Viewed by 7186
Abstract
Messenger RNA (mRNA) vaccines have redefined cancer immunotherapy, offering unparalleled flexibility to encode tumor-specific antigens and to be adapted to individual mutational landscapes. Melanoma, with its high mutational burden and responsiveness to immune checkpoint blockade, has become the leading model for translating these [...] Read more.
Messenger RNA (mRNA) vaccines have redefined cancer immunotherapy, offering unparalleled flexibility to encode tumor-specific antigens and to be adapted to individual mutational landscapes. Melanoma, with its high mutational burden and responsiveness to immune checkpoint blockade, has become the leading model for translating these advances into clinical benefit. Recent innovations in delivery—ranging from lipid nanoparticles and polymeric carriers to biomimetic hybrids and intratumoral administration—are dismantling long-standing barriers of stability, targeting, and immunogenicity. Clinical milestones, including the randomized phase IIb KEYNOTE-942, show that adding the personalized neoantigen vaccine mRNA-4157 (V940) to pembrolizumab prolonged recurrence-free survival versus pembrolizumab alone (HR 0.561, 95% CI 0.309–1.017; 18-month RFS 79% vs. 62%), with the ASCO 3-year update reporting 2.5-year RFS 74.8% vs. 55.6% and sustained distant metastasis-free survival benefit in resected high-risk melanoma. Parallel preclinical studies highlight the potential of multifunctional platforms co-delivering cytokines or innate agonists to reshape the tumor microenvironment and achieve durable systemic immunity. As artificial intelligence drives epitope selection and modular manufacturing accelerates personalization, mRNA vaccines may have the potential to transition from adjuncts to main therapies in melanoma and beyond. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
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