Though subclinical melanoma metastases have been found in many parts of the body, clinically detectable distant metastases are usually limited to skin, lung, brain, liver, bone, and intestine
[65][3]. This suggests that tumor microenvironments play a significant role in melanoma metastasis. Further supporting this is the observation that some patients developed melanoma metastases after receiving organ transplants from supposedly disease-free individuals with a history of melanoma, ostensibly resulting from reactivation of the donor’s dormant metastatic disease
[65][3]. A recent study by Tirosh et al. using single-cell RNA sequencing to analyze the transcriptome of melanoma tumors found that the tumor microenvironment is shaped by the intra- and interindividual spatial, functional, and genomic heterogeneity of melanoma and the associated tumor components
[64][2]. A later study by Thrane et al. using in situ transcriptome analysis showed intra- and intertumoral gene expression heterogeneity in lymph node metastases. They also found that lymphoid tissue gene expression programs were potentially influenced by their distance from tumor cell clusters. In lymphoid tissues far away from tumor cell areas expression of the immune-related gene CD74 was observed while in tissues in close proximity to tumor cell areas, expression of the immune-related gene IGLL5 was seen. In the tumor cell cluster, PMEL and SPP1 were overexpressed
[107][41]. It is thought that components of the adaptive immune system inhibit metastasis while innate immune system cells, such as macrophages, assist in mediating metastasis
[65][3]. Overexpression of αvβ3/αIIbβ3 integrins on melanoma cells, which is mediated by EMT-TFs, is known to be associated with metastasis and the switch from RGP to VGP
[81,108][25][42]. αvβ3-integrin has also been found to mediate extracellular matrix degradation and regulate the expression PD-L1, therefore promoting immune evasion
[81][25]. Autocrine motility factor (AMF), a cytokine that is secreted from tumor cells, has been shown by Tímár et al. to be linked with in vivo spontaneous metastatic potential and greater β3 integrin expression
[109][43]. CD44, a cell surface adhesion receptor that participates in lymphocyte activation as well as other immune functions, has also been linked with melanoma metastasis. Döme et al. found that the five year survival of patients with melanomas greater than 1mm thickness was significantly lower for those positive for the CD44v3 splice variant than those that were negative
[110][44]. Other metastasis-associated factors on melanoma cells that affect the tumor microenvironment include MCAM/MUC18, L1-CAM, α4β1-integrin, ECM remodeling molecule FN1, and glypican-6
[81][25]. Melanoma is known to evade the immune system by increasing expression of PD-L1 (ligand for the T cell PD-1 receptor) on melanoma cells and CTLA-4 (an immune suppressive protein) on T cells. Their increased expression promotes immunosuppressive activity, such T cell anergy, Treg differentiation, and tumor infiltrating lymphocyte apoptosis. Progression is associated with the presence of Treg cells due to their ability to help melanoma avoid immune surveillance through the secretion of cytokines and chemokines (CXC) with immunosuppressive actions, such as IL-10, IL-35, and TGF-β. Melanoma also suppresses the immune system by expressing immune inhibiting miRNAs, depriving T cells of arginine and tryptophan, inhibiting natural killer cell and macrophage function through high levels of adenosine, inhibiting natural killer cell activity and APC immunogenicity through high levels of kinurenine, and the secretion of exosomes that modulate the tumor microenvironment. The immune evasion strategies have been covered in greater detail in previous reviews
[111][45]. NRAS, KIT, EGFR, MET, RAB27A, and other pro-progression proteins have all been found within exosomes released by melanomas
[112][46]. Melanoma exosomes are able to promote invasion, angiogenesis, and metastasis in receiving tumor cells
[112][46]. They are also able to create premetastatic niches in the body
[112][46]. Melanoma metastases are known to favor colonizing areas with higher exosomes and sentinel lymph nodes were found to have very high levels
[112][46]. Lymph metastases are known to often precede the discovery of those in the blood and distant sites. A recent finding is that lymph prevents ferroptosis and reduces oxidative stress in metastasizing melanoma cells
[113][47]. This is due to the reduced levels of free iron and elevated levels of glutathione and oleic acid in the lymph as compared to the blood
[113][47]. They also discovered that melanoma cells that were previously exposed to lymph survived better in blood than those that had no exposure since they incorporated the antioxidants from the lymph
[113][47]. Melanoma also has the ability to perform platelet and vasogenic mimicry. Platelet mimicry is characterized by the expression of the megakaryoctic factors and the GPCR PAR1 (protease activating receptor 1) is associated with this
[114][48]. Future studies should continue elucidating novel factors affecting the tumor microenvironment and promoting metastasis.