The literature indicates that the addition of EVs to a human cell culture enhances EV production and supports cell proliferation [20]. The biodistribution of cancer-derived EVs in tumor tissues is an important factor in determining the role of EVs in tumor proliferation [26]. In vivo experiments have shown that B16BL6 melanoma cells secrete and absorb B16BL6 cell-secreted EVs to induce their own proliferation and inhibit their own apoptosis, promoting tumor progression [27]. EV uptake by target cells relies on the integrity of plasma membrane microdomains, namely lipid rafts, which are known to be enriched with cholesterol. Scavenger receptor type-B1 (SR-B1) is a high-affinity receptor for mature high-density lipoproteins (HDLs), and SR-B1 maintains cholesterol equilibrium, uptakes extracellular material, and promotes cell signaling [28,29]. The expression of SR-B1 in melanoma enhances EV formation and cellular uptake, promoting a metastatic phenotype. SR-B1 is associated with the expression of microphthalmia-associated transcription factor (MITF) and the regulation of proto-oncogene mesenchymal-to-epithelial transition (MET) factor. SR-B1 is a key molecule for regulating EV uptake and cancer growth [30]. Wnt Family Member 5A (WNT5A) regulates the release of EVs containing the immunomodulatory cytokine IL-6 and proangiogenic factors IL-8, VEGF, and MMP2 from melanoma cells (MeWo, SKmel28, A2058, A375, and HTB63). This effect increases angiogenic processes and facilitates metastatic spread [31]. Hood et al. indicated that melanoma EVs can boost endothelial angiogenic responses to create a premetastatic niche [32]. A previous report indicated that miR-155 in melanoma-derived EVs can induce reprogramming of fibroblasts into CAFs (cancer-associate fibroblast) and trigger the proangiogenic switch of these CAFs [33].

Studies on melanoma cell migration and invasion and on the underlying molecular mechanisms are essential for improving melanoma diagnosis, prognosis, and therapy. EVs play an important role in this regard and regulate the migratory and invasive capacity of melanoma cells. Several studies have demonstrated that EVs can increase migratory and invasive capacities [34]. EVs derived from melanoma cells have also been shown to increase type I interferon receptor (IFNAR1) and cholesterol 25-hydroxylase (CH25H) in normal cells, thus facilitating EV uptake and pre-metastatic niche development [35]. Matrix metalloproteinases (ADAM) and ADAM with thrombospondin motifs (ADAMTS) are enriched in melanoma-derived EVs. These proteins are critical for degrading the extracellular matrix of cancer cells and increasing metastatic spread [36]. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is a multifunctional RNA-binding protein that has been linked to the development of a variety of malignancies. According to previous research, EVs derived from IGF2BP1-overexpressing melanoma cells exacerbate EV-induced metastasis [37]. Xiao et al. showed an increase in invasiveness when normal melanocytes were treated with melanoma EVs [38]. Melanoma usually metastasizes to the lungs, bones, liver, and brain and rarely to other organs. The current mechanism of this pattern needs further understanding, but it is likely that EVs play an important role. For example, melanoma cells are exposed to bone-derived soluble factors, which are related to the molecular activation pathway of stromal-cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4)/type 7 CXC chemokine receptor (CXCR7). To this end, EVs reprogram the innate osteotropism of melanoma cells by upregulating their CXCR7 expression [39]. These results suggest that melanoma-cell-derived EVs contribute to melanoma metastasis. In addition, adipocytes secrete EVs, which are oxidized by fatty acids and are absorbed by tumor cells, resulting in increased metastasis and invasion of melanoma [40]. EVs from melanoma cells with poor metastatic potential potently inhibit metastasis to the lung and trigger immune surveillance, resulting in the elicitation of a broad range of monocyte (PMO)-reliant innate immune responses. Furthermore, Plebanek et al. suggested that cancerous cells are cleared at the pre-metastatic niche [41].

The interactions of cancer cells with their environment determines whether the primary tumor is contained, metastasizes, or establishes dormant micrometastases. EVs play essential roles in the interstitial transport and intercellular communication within the tumor microenvironment (TME). Metastatic tumor cells show increased ability to sort EV cargo (i.e., proteins and microRNAs) and to release EVs. EV cargo is then transferred to stromal cells, including those that are present in premetastatic niches. Furthermore, EVs promote tumorigenesis and invasion through a variety of mechanisms, resulting in premetastatic niche formation. The following table describes the roles of EVs in the TME [42] (Table 1).

The tumor microenvironment controls immune surveillance and anti-tumor immunity [49], mainly through intra- and extracellular signaling. Immunoediting is a complex process that includes intra- and extracellular signals. EVs play an important role in immune escape, both directly and indirectly. The direct modulation of either immune cells or their immature precursors is mostly driven by EV-mediated anti-apoptotic or pro-apoptotic signaling during the melanoma cell migration. The indirect roles of EVs include the expansion and differentiation of negative regulators of the immune system, such as myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs), thus promoting tumor cell escape from immune surveillance [50,51]. Several effects, i.e., mechanisms link EVs and the immune system (Table 2). Studies have shown that EVs secreted by tumor cells protect and maintain the growth of cancer cells, while EVs produced by normal cells, especially stem cells, inhibit tumor growth and suppress cancer progression [52]. Homing of melanoma exosomes to sentinel lymph nodes imposes synchronized molecular signals that effect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes [53]. In addition, tumor-derived EVs were shown to interfere with immunization by inducing loss of antigen expression, suppression of immune effector cells, exchange of nucleic acids, changes in recipient cell transcription, and inhibition of the immune cell response [54]. Other studies point out that tumor cells and tumor-infiltrating immune cells form a highly tolerant microenvironment, increasing tumor growth and allowing metastatic spread. Studies of anti-tumor immunity have explored the host’s immune responses and promote the development of new therapies and novel methods for use in future therapeutic methods [55].

EVs are involved in the development and regulation of different cancer-related processes. Drug resistance of cancer cells is a huge clinical problem and requires further investigation. Nevertheless, it is known that drug-resistant tumor cells are able to enclose chemotherapeutic agents in EVs and transfer anticancer drugs out of tumor cells. Therefore, understanding the molecular mechanisms and signaling pathways of EV-mediated drug resistance will help in the design of novel cancer treatments.

A large number of studies indicate that EVs play a crucial role in the development of the drug resistance of cancer cells (Table 3). Previous research has indicated that the use of BRAF kinase inhibitors (vemurafenib and dabrafenib) to treat melanoma patients bearing the BRAF-activating mutation V600E results in tumor regression, followed by quick development of drug resistance. Receptor tyrosine kinases (RTKs) are upregulated and activate the PI3K-Akt signaling pathway. EVs from drug-resistant melanoma cells were enriched with the RTK PDGFRβ, and delivering EVs rich in PDGFRβ to metastatic melanoma cells with the BRAF inhibitor-sensitive phenotype activated the PI3K/AKT pathway and resulted in the development of drug resistance [64]. Moreover, a novel truncated form of anaplastic lymphoma kinase (ALK) named ALK^RES was found to be secreted in EVs. The transfer of ALK^RES to sensitive, ALK-negative melanoma cells caused activation of the MAPK signaling pathway and transferred the characteristics of drug resistance to the recipient cells [65].

MicroRNAs (miRNAs) constitute a class of small single-stranded noncoding RNAs (~22 nt in length) that suppress gene expression. miRNAs are transcribed in the nucleus by RNA polymerase II or III. Primary miRNA transcripts (pri-miRNAs) are cleaved through a complex that consists of the endonuclease Drosha and the RNA-binding protein DGCR8. Hairpin pre-miRNAs are exported to the cytoplasm and are cleaved by the endonuclease Dicer to form dsRNA–miRNA duplexes. The complementary strand of the mature miRNA sequence is degraded, facilitating miRNA-induced silencing complex (RISC) formation and targeting the complementary sequences in the 3′ UTR of target mRNAs inhibit translation. miRNAs regulate many physiological and pathophysiological processes, such as growth, differentiation, and cancer progression. miRNAs regulate hundreds of genes; thus, miRNAs can cause complex phenotypic changes [66]. The loss of certain miRNAs facilitates cancer growth, whereas overexpression of other miRNAs promotes cancer progression [67]. miRNAs change the phenotype of melanoma cells and metabolic pathways during melanoma progression. They also affect the extracellular matrix (ECM), which includes fibroblasts, endothelial cells, and immune system cells [68]. miRNAs have different functions in each step of the development of different cancers [69]. Cells have the ability to selectively sort miRNAs into EVs for secretion to nearby or distant targets. Moreover, certain disease states have also identified dysregulated EV-miRNA content, shedding light on the potential role of selective sorting in pathogenesis. The latest findings regarding the roles of EVs-relevant miRNAs in melanoma pathobiology are summarized in Table 4.