Search Results (147)

Background: Circulating cell-free DNA (cfDNA) enables minimally invasive tumour genomic profiling, yet simultaneous interrogation of mutations and DNA methylation remains limited by assay complexity and input constraints. Methods: Here, we evaluate the Agilent Avida Duo system, a single workflow integrating high-sensitivity mutation detection with targeted DNA methylation analysis. We analysed 21 stage III and IV melanoma patient samples. Results: The Avida Duo mutation assay detected mutant allele frequencies (MAFs) down to 0.05% and identified tumour-associated mutations in all melanoma patients, including within GC-rich regions such as the TERT promoter. Optimisation of the Avida Duo mutation workflow, using TapeStation-quantified cfDNA and reduced amplification cycles, improved library consistency without compromising sensitivity. Methylation profiling of the melanoma baseline cohort with the Avida Duo methylation panel showed high concordance with QIAseq targeted methylation results, with the mean cfDNA fraction methylation ranging from 0.051–0.079 in most patients and reaching 0.249 in the patient with the highest ctDNA burden (MAFs up to 35.4%). Conclusions: Our findings demonstrate that the Avida Duo workflow enables simultaneous, high-resolution detection of mutation and methylation profiles from a single cfDNA sample, streamlining processing and enhancing molecular insight for clinical and translational applications. Full article

Background/Objectives: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with a 40% recurrence rate. However, reliable biomarkers for early recurrence detection or treatment guidance are lacking, especially for virus-negative tumors. Circulating tumor DNA (ctDNA), a fragment of tumor-derived cell-free DNA in blood, has emerged across multiple cancers as a minimally invasive precision biomarker to detect minimal residual disease (MRD); predict recurrence; and monitor treatment response. This review’s objective was to summarize recent advances in ctDNA as a tool for therapeutic decision-making in MCC, contextualized by findings in other malignancies. Methods: A comprehensive literature review was performed, focusing on studies published between 2016 and 2026 that evaluate ctDNA in MCC and other cancers. Key prospective trials, observational studies, and case reports were identified through PubMed and relevant conference proceedings. Data on ctDNA assay methods (tumor-informed vs. tumor-agnostic), clinical sensitivity, lead time for recurrence detection, and predictive value for therapy response were extracted and synthesized. Results: Across cancers such as colorectal, lung, and melanoma, ctDNA positivity after curative treatment predicts relapse months in advance of imaging and can guide adjuvant therapy decisions. In MCC, recent studies demonstrate that ctDNA levels correlate with MCC tumor burden and exhibit high sensitivity and specificity for clinically evident disease. Stage I-III MCC patients who were ctDNA-positive within four months of treatment had a 7.4-fold higher recurrence risk within the subsequent 12–18 months of follow-up. Serial ctDNA monitoring may enable earlier intervention in otherwise asymptomatic ctDNA-positive MCC cases, helping distinguish responders from non-responders. Conclusions: ctDNA is an emerging precision biomarker that offers significant prognostic and surveillance utility in MCC. It enables earlier detection of recurrence, potentially allowing treatment to begin before clinical disease manifests. It also helps stratify patients by risk and treatment response, informing personalized surveillance intensity and therapeutic choices. Integrating ctDNA monitoring into MCC management could improve outcomes by guiding timely interventions, although prospective trials are needed to confirm that ctDNA-guided decisions translate to improved patient survival. Formal cost-effectiveness analyses have not yet been conducted and represent an important area for future investigation. Full article

Melanoma has long represented a unique challenge in oncology. In its early stages, it can often be cured with surgery alone, resulting in excellent survival outcomes. Its biology is complex and heterogeneous, often including mutations such as BRAF and NRAS, which partly explain its high immunogenicity but also its capacity to relapse. For many decades, the standard approach in resectable stage III melanoma was surgery first, followed by adjuvant therapy. In the last decade, the development of immune checkpoint inhibitors created the opportunity to treat patients before surgery. The neoadjuvant approach is based on the hypothesis that treatment of the intact tumor may enhance antitumor immune priming and activation. The first prospective neoadjuvant studies, including OpACIN and OpACIN-neo, showed high pathological response rates with ipilimumab plus nivolumab and introduced pathological response as an early marker of long-term benefit. The PRADO study showed that treatment response could guide the extent of surgery required. The SWOG S1801 trial demonstrated better event-free survival with perioperative pembrolizumab compared to adjuvant therapy alone. Lastly, the phase III NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy significantly improves outcomes. Biomarkers such as PD-L1, IFN-γ signature, tumor mutational burden and imaging (PET scan) appear promising to predict response, but none have been sufficiently validated for routine clinical practice. Full article

Objectives: To describe the scientific evidence regarding adjuvant treatment for stage III and IV cutaneous melanoma and the unresolved issues in this setting. Methods: This review examines the main studies on adjuvant medical therapies approved over the years by the Food and Drug Administration and European Medicines Agency together with the main evidence related to the treatments referred to in the National Comprehensive Cancer Network and European Society of Clinical Oncology guidelines at the time of submission (May 2026) for stage III and IV cutaneous melanoma. A particular focus on immunotherapy (interferon, ipilimumab, and anti-PD-1 antibodies, both as monotherapy and in combination) and targeted therapy with anti-BRAF agents, either as monotherapy or in combination with MEK inhibitors, is given. Besides that, this work also evaluates the role of radiation therapy and addresses some unresolved issues, such as adjuvant therapy in stage IIIA and treatment selection in BRAF-mutated melanoma. Results: Adjuvant therapy for stage III and IV cutaneous melanoma has evolved over the years, starting with interferon and progressing to the use of immunocheckpoint inhibitors and targeted therapy. However, not all treatments that have proven effective in metastatic disease have subsequently played a role in the adjuvant setting. Conclusions: Currently, adjuvant treatment for stage III and IV cutaneous melanoma involves the use of anti-PD-1 antibodies (nivolumab and pembrolizumab) and dabrafenib plus trametinib if the patient has a BRAF V600 mutation. It was not possible to identify the adjuvant therapy of choice for BRAF-mutated melanoma, and several factors must be considered when deciding between immunotherapy and targeted therapy. The role of radiation therapy remains controversial and could be discussed by the multidisciplinary team as part of the adjuvant strategy in selected patients. Likewise, adjuvant therapy for stage IIIA melanoma should be carefully evaluated in light of the risk–benefit ratio. Full article

Background: Elderly patients have low utilization of adjuvant ICIs, although they achieve similar RFS benefits as younger patients. It remains unclear why elderly patients use adjuvant ICIs less frequently and whether toxicity impacts treatment utilization. Methods: Adult patients with stage III melanoma treated from 2017 to 2023 at a single academic cancer center were retrospectively identified. Multivariable logistic regressions evaluated the association of age with receipt of adjuvant ICIs and toxicity. RFS was assessed using Kaplan–Meier and multivariable Cox proportional hazards regression. Results: Among 240 patients, those aged ≥ 75 years were less likely to receive adjuvant ICI than those aged 18–74 years (aOR: 0.30; 95% CI: 0.11–0.80). Among 53 (22.1%) patients who did not receive adjuvant ICI, 58% declined treatment, 15% were not offered adjuvant ICI by provider, 9% had a comorbid autoimmunity, and 6% had another comorbidity. A total of 12% of patients aged 75–80 years old declined treatment versus 33% of those aged 80–90 years old. Older age was not associated with toxicity, treatment interruption, or discontinuation from adjuvant ICI. Adjuvant ICI was associated with low recurrence (aHR: 0.76; 95% CI: 0.63–0.92), whereas age ≥ 75 years was associated with higher recurrence risk (aHR: 1.79; 95% CI: 1.04–3.10) and low overall survival (aHR: 3.07; 95% CI: 1.43–6.57) compared to patients aged 18–74 years. Conclusions: Older patients with stage III melanoma were less likely to receive adjuvant ICIs, despite similar toxicity, treatment interruption, and discontinuation rates across age groups. Because adjuvant therapy is associated with lower recurrence risk, efforts to better understand and address age-related differences in treatment use are warranted. Full article

The role of adjuvant therapy in stage III melanoma is well established in clinical practice. Because stage IIB–IIC melanoma carries a risk of recurrence and melanoma-specific mortality comparable to that of stage III disease, adjuvant approaches have also been developed for patients with thick stage II tumors. Both pembrolizumab and nivolumab have demonstrated efficacy in reducing the risk of local and distant recurrence in patients with high-risk stage II melanoma, whereas evidence supporting the use of BRAF-MEK inhibitors in this setting remains inconclusive. Combinations of immune checkpoint inhibitors, as well as immunotherapy combined with mRNA-based vaccines, are currently under investigation in clinical trials. However, given the non-trivial risk of immune-related adverse events, careful selection of patients with stage II disease who are most likely to derive meaningful benefit from adjuvant therapy is essential. In this context, several clinicopathologic variables and gene expression profiling-based prognostic tools have been proposed to refine risk stratification. To date, however, none of these instruments have been incorporated into routine clinical practice, and no validated predictive biomarkers are available. Accordingly, optimal patient selection for adjuvant therapy remains an important unmet clinical need in early-stage melanoma. Full article

Background/Objectives: This study evaluates the prognostic value of baseline inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in advanced cutaneous melanoma treated with first-line immunotherapy. Methods: This multicenter retrospective study included 162 patients with unresectable stage III/IV cutaneous melanoma treated with first-line pembrolizumab, nivolumab, or nivolumab plus ipilimumab. Biomarkers were calculated from complete blood counts obtained within 30 days before treatment start. Cut-offs were defined by ROC analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression. Response was assessed by RECIST v1.1. Results: Higher baseline NLR, PLR, MLR, SII, and PIV were more common in patients with adverse baseline features, including liver metastases, elevated LDH, and poorer ECOG performance status. Patients with biomarker values below the cut-offs had significantly longer PFS and OS. In biomarker-specific multivariable models adjusted for selected clinical covariates, PIV retained the most consistent association with PFS and OS, while MLR was associated with PFS, and PLR with OS. Conclusions: Baseline inflammatory biomarkers from routine blood counts provide useful prognostic information in advanced melanoma treated with first-line ICIs. PIV showed the most consistent association with survival outcomes and may support initial risk stratification alongside LDH, ECOG, and metastasis pattern. However, prospective validation in independent cohorts is needed before routine clinical implementation. Full article

Background and Objectives: Tumor-infiltrating lymphocytes (TIL) and the neutrophil-to-lymphocyte ratio (NLR) are each associated with prognosis in melanoma, yet their combined prognostic value remains insufficiently defined. We aimed to assess whether integrating NLR and TILs into a combined immune phenotype improves prediction of recurrence-free survival (RFS) in patients with resected cutaneous melanoma. Materials and Methods: A total of 203 patients were included. Receiver operating characteristic analysis identified an NLR cut-off of 2.75 for RFS, defining low (<2.75) and high (≥2.75) groups. TIL status was dichotomized as present or absent. According to the combined NLR–TIL profile, patients were initially categorized into three immune phenotypes: favorable (low NLR and TIL-positive), intermediate (low NLR and TIL-negative or high NLR and TIL-positive), and unfavorable (high NLR and TIL-negative). For the dichotomized analysis, the intermediate and unfavorable phenotypes were combined and compared with the favorable phenotype. Associations of clinicopathological factors with RFS were evaluated using Kaplan–Meier curves and Cox regression models. Results: The median follow-up was 56 months. In the univariate analysis, stage III disease, greater Breslow thickness, increased mitotic rate, and absence of adjuvant therapy were associated with worse RFS. In addition, patients with an unfavorable immune phenotype had a markedly increased risk of recurrence compared with those in the favorable group (HR 2.86, 95% CI 1.43–5.71; p = 0.004). In multivariate Cox regression analysis, both the unfavorable immune phenotype and stage III disease independently predicted RFS (HR 2.25, 95% CI 1.11–4.54; p = 0.024 and HR 2.13, 95% CI 1.03–4.43; p = 0.041, respectively). Conclusions: Combined assessment of systemic inflammation and tumor-local immune response using NLR and TILs may provide meaningful prognostic stratification in resected cutaneous melanoma. Full article

Melanoma is a heterogeneous, complex and aggressive disease that, despite recent advances in molecular-targeted drugs and molecular and genetic analysis, represents approximately 65% of skin cancer deaths, and unfortunately survival dramatically decreases in melanoma stages III/IV. In young people there is an increased incidence of developing melanoma; hence new therapeutic strategies must be urgently investigated. Peptidergic systems play a crucial role in these strategies to fight melanoma. The scope of this review is to show the enormous potential of targeting peptidergic systems alone or in combination therapy with standard therapeutic strategies currently used in clinical practice to treat melanoma. In this sense, key points such as peptidergic systems and anti-melanoma treatments, oncogenic/anti-melanoma peptides, peptide receptors, peptidergic systems, melanoma risk and immune system relationships, clinical relevance, peptidergic systems and delivery strategies in melanoma will be discussed. Peptides exert oncogenic, anti-melanoma and dual oncogenic and anti-melanoma effects in melanoma, showing a high functional complexity in regulating melanoma development. A plethora of anti-melanoma strategies have been developed or repurposed for potential clinical applications, including peptide/peptide receptor antibodies, peptide receptor antagonists or agonists, enzyme inhibitors, CAR-macrophages, microRNAs and vaccines. Strategies for peptide delivery and protection from enzymatic degradation have also been developed. Some of the previous anti-melanoma strategies are based on the expression/overexpression of peptide receptors in melanoma cells which is crucial for diagnosis, melanoma risk and progression and metastasis development and for the application of more specific and safer anti-melanoma strategies. A meticulous and in-depth study of the peptidergic systems may help to understand how peptidergic systems regulate melanoma progression and shed light on possible therapeutic applications that can be applied in clinical practice. This review shows the enormous potential of targeting peptidergic systems alone or in combination therapy with standard therapeutic strategies currently used in clinical practice to treat melanoma. The benefits to be gained from these studies will be enormous because the peptidergic systems are promising antitumor targets in melanoma, based on the numerous anti-melanoma strategies that have been developed until now. Full article

Background/Objectives: During the pandemic, access to healthcare was severely disrupted, inevitably affecting melanoma diagnosis. While this was clearly evident during the pandemic itself, it is less clear whether clinical presentation has returned to baseline levels in subsequent years. Our study aimed to compare the current clinical presentation of melanoma with that in the pre-pandemic setting. Methods: We conducted a retrospective multicenter study involving Italian melanoma referral centers within the SICO network. Patients with a newly diagnosed primary cutaneous melanoma were included in the study and were grouped into four time periods: pre-pandemic (March 2019 to February 2020); pandemic (March 2021 to February 2022); the first post-pandemic year (March 2022 to February 2023); and the second post-pandemic year (March 2023 to February 2024). Our focus was on clinically relevant features at diagnosis, including Breslow thickness, ulceration, stage and sentinel lymph node status. We evaluated differences across periods using regression models that accounted for the multicenter design. Results: A total of 4938 patients were included in the study. Compared with the pre-pandemic period, melanomas diagnosed during and after the pandemic were thicker, more frequently ulcerated and more likely to be in stages II–III. The rate of sentinel lymph node positivity also increased. Notably, these patterns did not normalize over time, remaining evident even in the second post-pandemic year. The results were consistent after adjusting for age and sex. Conclusions: In this large Italian study, melanoma continues to be diagnosed at a later stage than in the pre-pandemic period. This persistent shift may reflect a combination of delayed access to care and ongoing system-level constraints. These findings emphasize the importance of restoring timely access to dermatological evaluation and reinforcing early detection strategies. Full article

Uveal melanoma (UM) lacks minimally invasive and reproducible biomarkers to support clinical risk stratification, motivating the need for molecular profiling of aqueous humor (AH) as an alternative to fine-needle tumor aspiration (FNAB). This study aimed to generate a calibrated AH protein concentration map to identify tumor-associated signals present at clinically measurable levels and assess their associations with established molecular and clinical features. AH samples from 70 UM eyes were analyzed using next-generation sequencing-based proximity extension assays (PEAs), and leftover AH from 27 samples was further assessed using qPCR-based PEA to obtain reference concentration values. Regression models derived from overlapping proteins enabled extrapolation of calibrated pg/mL-level concentrations across the full cohort. Twenty-three proteins had median modeled concentrations above 5 pg/mL and were examined for clinical relevance and translational feasibility. Several proteins, including CXCL8, CXCL10, VEGFA, HGF, PDCD1, FLT1, FLT3LG, and CCL2, showed progressive increases from GEP1/PRAME− to GEP2/PRAME+ tumors and from AJCC Stage I/II to Stage III/IV, with Stage IV tumors demonstrating significant elevations in CXCL8, VEGFA, and PDCD1. Pathway analysis revealed activation of inflammatory and tumor microenvironment pathways, and upstream regulator analysis identified VEGFA and CCL2 as potential drivers. These findings demonstrate that calibrated AH proteomic profiling can identify clinically measurable protein changes associated with UM risk and stage, supporting its potential utility for biomarker development. Full article

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. Results: Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I² ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02–1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36–2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61–2.51; MVA PFS HR 1.49, 95% CI 1.18–1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79–2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53–1.91; MVA PFS HR 1.61, 95% CI 1.41–1.85), whereas body mass index (BMI) > 25 kg/m² was associated with improved OS (HR 0.82, 95% CI 0.68–0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16–2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40–4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30–2.20; MVA PFS HR 1.52, 95% CI 1.00–2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25–3.44) and PFS (UVA HR 2.97, 95% CI 1.39–6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63–5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33–0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14–0.47; UVA PFS HR 0.50, 95% CI 0.34–0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31–9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96–11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. Discussion: This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes. Full article

Background and Objectives: High-risk resected cutaneous melanoma carries a substantial risk of recurrence, and additional host-related prognostic biomarkers are needed beyond conventional tumor-centered factors. Red blood cell distribution width (RDW) reflects systemic inflammation and physiological stress and may provide incremental prognostic information. Materials and Methods: In this retrospective cohort study, 164 patients with stage II–III cutaneous melanoma who underwent curative-intent surgical resection were analyzed. A receiver operating characteristic (ROC) curve analysis determined the optimal RDW cut-off for relapse-free survival (RFS), which was 14.2%. Patients were categorized into low and high RDW groups accordingly. Survival probabilities were estimated using the Kaplan–Meier method and compared with the log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to evaluate associations between RDW status, clinicopathological variables, and RFS. Results: During a median follow-up of 58.3 months, patients with high RDW had significantly shorter RFS compared with those with low RDW. In univariate analysis, elevated RDW was associated with an increased risk of recurrence (HR 2.79, 95% CI 1.39–5.58; p = 0.004). After adjustment for key prognostic factors (e.g., stage, Breslow, age, adjuvant therapy), high RDW remained an independent predictor of inferior RFS (HR 2.74, 95% CI 1.37–5.47; p = 0.004). Stage III disease also independently predicted worse RFS (HR 4.67, 95% CI 2.04–10.68; p < 0.001). Conclusions: Baseline RDW independently predicts RFS in high-risk resected stage II–III cutaneous melanoma and may enhance prognostic stratification using a simple, widely available biomarker. Full article

Background/Objectives: Malignant melanoma is a highly aggressive cancer associated with significant mortality, underscoring the need for continued research efforts. COMBI-EU (NCT03944356) is a prospective, non-interventional study that aims to assess adjuvant dabrafenib and trametinib usage in clinical practice, the impact of AE management, and the usage of app-based documentation on treatment adherence. Methods: Adults with complete surgical resection of stage III BRAF V600-mutant cutaneous melanoma were included. The primary endpoint was median time on treatment (TOT). Adverse event (AE) management was classified as either a high or low level of management. The rating of AE management based on a self-developed algorithm and rules from COMBI-APlus was used to analyze the impact of AE management on TOT. App-based documentation of medication intake and patient-reported outcomes (CANKADO PRO-React; version 6.0, 06.03.2019) was offered. Results: For 225 patients, the median TOT was 11.8 months (95% confidence interval [CI]: 11.7, 12.0). Treatment was completed by 138 patients (61.3%); 37 (16.4%) discontinued due to treatment-related AEs (TRAEs). TRAEs (≥1) were experienced by 181 patients (80.4%); the most common was pyrexia (38.2%). High-level AE management showed a trend toward improved treatment adherence (high versus low level: hazard ratio [HR]: 0.74; 95% CI: 0.49, 1.14); this improvement was significant with pyrexia management (HR: 0.52; 95% CI: 0.29, 0.93). Seventy-nine (35%) and 33 patients (15%) intended to use and eventually used the app, respectively. A similar proportion of patients remained on treatment for 12 months irrespective of app usage (use, 39.4% vs. non-use, 36.5%). Conclusions: High-level TRAE management showed a trend toward improved treatment adherence, which was statistically significant for pyrexia. Optional use of an app did not influence treatment adherence. Full article

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