HMGB1, after being released from damaged or necrotic cells, is used by the immune system to recognize tissue damage in order to initiate repair responses and to promote lymphocyte maturation [16]. From here, we can deduce a role in oncological diseases [16]. One of the important stages of disease progression is neoangiogenesis, which is fundamental for sustaining the metabolic and oxygen demands of cancer cells. It is known that solid tumors exhibit large hypoxic areas because of an imbalance between their oxygen supply and consumption. This hypoxic environment results in focal areas of tumor cell necrosis with consequent release of DAMPs and alarmins, including HMGB1 [17]. Extracellular HMGB1, released from the tumor cells under hypoxia, mediates communication between cells in the tumor microenvironment through binding several receptors, especially RAGE and TLR4, which contribute to tumor growth via sustenance of long-term inflammation [16]. Once secreted by melanoma cells, HMGB1 binds to RAGE, activating the endothelial cells with consequent increased expression of the adhesion molecules VCAM-1, ICAM-1, and E-selectin [16]. Within the tumor necrotic zones, the release of HMGB1 leads to the activation of kappa-light-chain-enhancer of activated B cells (NF-κB), which in turn upregulates leukocyte adhesion molecules and the production of pro-inflammatory cytokines and angiogenic factors, including vascular endothelial growth factor (VEGF) [16]. Tumor-Associated Macrophages (TAMs) are recruited in the tumoral milieu characterized by the presence of chemokines and proinflammatory factors [18,19,20]. After tumor infiltration, macrophages can acquire two different phenotypes: the M1 phenotype exerts a cytotoxic effect on tumor cells, with increasing production of nitric oxide (NO) and reactive oxygen species (ROS), which mediate the apoptosis of neoplastic cells [21]. Tumor cells create a microenvironment that promotes the acquisition of an M2 phenotype, which possesses pro-tumor characteristics, and, in contrast to M1 phenotype, exhibits low cytotoxic properties with defective production of NO and ROS, promoting the growth and vascularization of tumor cells [21,22]. HMGB1, released by melanoma cells, promotes the accumulation of M2-macrophages, which enrich the tumoral microenvironment with IL-10, turning down the tumoral killing [22]. Further evidence that the production of HMGB1/RAGE-dependent IL-10 by macrophages promotes melanoma growth has come from a human melanoma tissue study, in which high infiltration of IL-10-producing macrophages was detected in melanoma tissue with a high expression of HMGB1 [17]. Since HMGB1 directly induces IL-10 production in TAMs, blocking IL-10 with a neutralizing antibody led to delayed tumor growth in a B16 mouse melanoma model [17]. RAGE/HMGB1 axis also activates T lymphocytes, as demonstrated by a study with animal specimens: the study showed that the HMGB1/RAGE axis influences melanoma growth via the expression of IL-23 and IL-17 from a subpopulation of T cells, (γδ-T cells) [23]. Growth of melanoma cell line B16-F10 was significantly inhibited, and expression of IL-23 and IL-17 was markedly reduced in RAGE−/− mice compared with wild-type mice. The same study also showed that HMGB1 stimulates the production of IL-23 in a RAGE-dependent manner, which in turn promotes the expression of IL-17; subsequently, IL-17 promotes tumor growth through IL-6 induction with the consequent activation of the Signal transducer and activator of transcription 3 (STAT3) [23]. In addition to promoting carcinogenesis, interleukin production, and shift of T cell subpopulation, the HMGB1/RAGE axis has been shown to play a key role in suppressing cytotoxic T cell activity by increasing PD-L1 expression levels [24,25]. Moreover, HMGB1 levels were higher in patients who did not respond to the immune checkpoint inhibitor ipilimumab than in responding patients, supporting the hypothesis that the HMGB1/RAGE axis also leads to a tumor-promoting microenvironment [26]. In addition, RAGE was detected in the cytoplasm of human melanoma cells (G361 and A375) and the treatment with AGEs induced the proliferation and migration of human melanoma cells. Thus, treatment with anti-RAGE antibodies could explain the inhibition of tumor formation, invasion, and increase in the survival rate of specimens in an in vivo animal model [27]. AGEs and RAGE could be a valuable target in the near future for the treatment of melanoma since their levels are abundantly inferior in healthy skin, thus suggesting that this type of therapy could have potentially very few side effects [28]. The main pathways involved in melanoma growth are represented in Figure 1.