Primary mucosal melanomas (MMs) are uncommon tumors originating from melanocytes located in the mucous membranes at various anatomic sites within the body. MM significantly differs from cutaneous melanoma (CM) regarding epidemiology, genetic profile, clinical presentation, and response to therapies. Despite these differences, that have important implications for both disease diagnosis and prognosis, MMs are usually treated in the same way as CM but exhibit a lower response rate to immunotherapy leading to a poorer survival rate. Furthermore, a high inter-patient variability can be observed in relation to therapeutic response. Recently, novel “omics” techniques have evidenced that MM lesions have different genomic, molecular, and metabolic landscapes as compared with CM lesions, thus explaining the heterogeneity of the response. Such specific molecular aspects might be useful to identify new biomarkers aimed at improving the diagnosis and selection of MM patients who could benefit from immunotherapy or targeted therapy. In this review, we have focused on relevant molecular and clinical advancements for the different MM subtypes in order to describe the updated knowledge relating to main diagnostic, clinical, and therapeutic implications as well as to provide hints on likely future directions.

Messenger RNA (mRNA) vaccines are emerging as promising tools capable of reshaping how cancer interacts with the immune system and responds to immunotherapy. These vaccines not only act as platforms for antigen delivery but can also influence the tumor microenvironment (TME), fostering a shift from immunologically “cold’’ conditions toward “hotter’’ and treatment-responsive states. In melanoma, this capability has been found to enhance the efficacy of the immune checkpoint inhibitors (ICIs), as mRNA-based priming can provide the robust antitumor activation needed for more effective checkpoint blockade. Early clinical studies with personalized or off-the-shelf vaccines showed benefits in patients with high-risk resected melanoma or refractory to PD-1 inhibition. Combining mRNA vaccines with ICIs, along with other immunomodulatory strategies, may be helpful to overcome resistance arising from the TME and achieve more durable clinical benefits. Besides these advances, computational and in silico modeling are providing new insights into how mRNA vaccines modulate the TME, helping to identify factors such as antigen-presenting cell (APC) density, CD8⁺ T-cell infiltration, and macrophage polarization that may predict treatment success and guide personalized strategies. Together, these developments indicate that combining mRNA vaccination with ICIs, supported by computational tools, may improve clinical outcomes in melanoma and, potentially, in selected tumor types with favorable immunological features, although important biological constraints limit direct extrapolation to less immunogenic malignancies.

Background: Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Recent therapeutic advancements have significantly improved clinical management, underscoring the importance of routine molecular profiling to guide personalised treatment strategies. This study aims to evaluate the prognostic impact of main molecular alterations—including allele frequency (AF) of RAS mutations—on survival outcomes in a real-world hospital-based cohort of patients with metastatic CRC. Methods: A total of 208 consecutive patients with a histologically confirmed diagnosis of CRC and complete clinical, molecular, and survival data were retrospectively analysed. Somatic mutations in KRAS, NRAS, BRAF, and the occurrence of microsatellite instability (MSI) were assessed using pyrosequencing and real-time PCR assays, respectively, on formalin-fixed, paraffin-embedded tumour samples. Associations between mutational status, clinicopathological parameters, and overall survival (OS) were evaluated. Results: Overall, 138 patients (66.3%) harboured at least one somatic mutation: 115 (55.3%) in KRAS, 8 (3.8%) in NRAS, and 15 (7.2%) in BRAF. MSI was detected in 17/208 (8.2%) patients. A statistically significant improvement in OS was observed in patients lacking mutations in any of the three genes—referred to as wild-type (WT) patients—with BRAF mutated cases showing the worst survival (p = 0.041). Increasing age at the time of first-line therapy for advanced disease stage was associated with a statistically significant increase in the hazard of death (p = 0.031). Conclusions: In the advanced disease stage, RAS/BRAF wild-type colorectal cancers were significantly associated with a survival advantage.