Apart from non-coding RNA, m6A RNA methylation is another crucial chemical modification discovered in mRNA and non-coding RNA in eukaryotic cells,188,189 the process of which is dynamically regulated by a series of writers, readers, and erasers.190 In melanoma, the expression of m6A demethylase FTO is significantly upregulated to contribute to not only tumorigenicity but also increased response to anti-PD-1 blockade by orchestrating the expressions of PD-1, CXCR4, and SOX10.191 Other reports also provide evidence that m6A demethylase alkylation repair homolog 5 (ALKBH5) and methyltransferases METTL3/14 regulate the response to anti-PD-1 blockade by re-shaping tumor microenvironment through the regulation of metabolism and chemokine secretion.192,193 The role of m6A methylation in tumor-infiltrating macrophages and related impact on tumor progression have also been elucidated in melanoma. genes and immune checkpoints, as well as the mechanisms underlying the treatment resistance. Finally, the prospects and challenges in the development of melanoma therapy, especially immunotherapy and related ongoing clinical trials, are summarized and discussed. mutation. Patients with these risk factors are usually diagnosed at a young age and generally display superficially spreading melanoma around the trunk. Around the other, chronic sun exposure often leads to melanoma harboring mutation, without any involvement of nevi proneness. Apart from environmental UVR and some phenotypic characteristics in individuals that are associated with the PAC-1 carcinogenesis of cutaneous melanoma, some other factors are documented to be associated with non-cutaneous melanoma, especially trauma and chronic inflammation for acral melanoma. A previous study conducted by our group that involves 685 Chinese patients with melanoma has revealed a prominent correlation between acral melanoma and the history of trauma around the lesion.13 In addition, some reports also indicated the generation of acral melanoma after trauma or from lesions of infection and chronic ulcer.14C16 The pro-tumorigenic effect of trauma and chronic inflammation might result from the increased cytokines and ROS that can induce genetic instability or activate SIR2L4 oncogenic pathways in melanocytes.17 The therapeutic approaches of melanoma undergo a dramatic evolution in the past few decades due to the progress in the understanding of melanoma pathogenesis and thereby revolutionary advances of targeted therapies that specifically intervene mutant driver genes and immune checkpoints. Historically, there were only dacarbazine chemotherapy and high-dose interleukin-2 (IL-2) approved by Food and Drug Administration (FDA) as treatment brokers for metastatic melanoma before 2010. Interferon-2b (IFN-2b) was also employed as adjuvant agent, whereas the usage was largely limited due to the frequent occurrence of severe adverse effects.1,18 Since ten years ago, a series of therapeutic agents and combinatorial approaches have been approved by FDA, including immunotherapy (single-agent ipilimumab, nivolumab, pembrolizumab, and combination of ipilimumab and nivolumab), targeted therapy (single-agent vemurafenib and dabrafenib, combinations of dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib) as well as one intralesional modified oncolytic herpes virus talimogene laherparepvec (T-VEC) (Fig. ?(Fig.22 and Table ?Table11).1,18C21 The above-mentioned therapeutic approaches have gained evident and encouraging responses in treating patients with advanced melanoma and some of them have also been approved in the adjuvant setting. Compared to 10 years ago, the 5-12 months survival has gained considerable improvement from 5% to around 30% in patients with advanced melanoma who accept the combination of BRAF inhibitor and MEK inhibitor or single anti-PD-1 antibody.21C23 Although current therapies have revolutionized the standard of management for patients with advanced melanomas, low response rate and inevitable occurrence of treatment resistance retard forward improvement of therapeutic outcome.24 Therefore, it is necessary to understand the molecular mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to the innovations of more applicable therapeutic approaches and provide additional clinical options for melanoma therapy. Open in a separate windows Fig. 2 Timeline for FDA-approved therapies for metastatic melanoma. HD high-dose, Ipi Ipilimumab, T-VEC talimogene laherparepvec Table 1 FDA-approved therapies for melanoma and occurring more frequently in melanoma than other types of solid tumors. The substitution from valine to glutamic acid at codon 600 (V600E), which leads to constitutive activation of the kinase activity of BRAF protein and downstream MAPK pathway, can be detectable in ~50% of melanomas.25 Other variants including V600K, V600D, PAC-1 and V600R occupy around 12%, 5%, and 1% of mutations, respectively.26,27 The presence of mutations has great potential in predicting an unfavorable prognosis in melanoma patients.28,29 In other subtypes of melanoma like acral melanoma and mucosal melanoma, the incidence of mutation is around 20% and 6%, which is much lower than that in cutaneous melanoma.30,31 PAC-1 NRAS is a small GTP-binding protein belonging to Ras family and transduces upstream RTK activation to promote the activity of downstream Raf. The mutations of usually occur at G12, G13, and Q61 sites, and are found in around 25% of cases of PAC-1 melanomas.32 Compared to mutations lag behind. A recent study has identified STK19 as a novel NRAS activator by enhancing its phosphorylation and binding to downstream effectors..