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We expanded this knowledge by evaluating whether opsins, light- and thermo-sensing proteins, could display tumor-modulatory effects on melanoma cancer. Using different experimental approaches, we show that melanoma cell proliferation is slower in the absence of <jats:italic>Opn4<\/jats:italic>, compared to <jats:italic>Opn4<\/jats:italic><jats:sup>WT<\/jats:sup> due to an impaired cell cycle progression and reduced melanocyte inducing transcription factor (<jats:italic>Mitf<\/jats:italic>) expression. In vivo tumor progression of <jats:italic>Opn4<\/jats:italic><jats:sup>KO<\/jats:sup> cells is remarkably reduced due to slower proliferation, and higher immune system response in <jats:italic>Opn4<\/jats:italic><jats:sup>KO<\/jats:sup> tumors. Using pharmacological assays, we demonstrate that guanylyl cyclase activity is impaired in <jats:italic>Opn4<\/jats:italic><jats:sup>KO<\/jats:sup> cells. Evaluation of Tumor Cancer Genome Atlas (TCGA) database confirms our experimental data as reduced <jats:italic>MITF<\/jats:italic> and <jats:italic>OPN4<\/jats:italic> expression in human melanoma correlates with slower cell cycle progression and presence of immune cells in the tumor microenvironment (TME). Proteomic analyses of tumor bulk show that the reduced growth of <jats:italic>Opn4<\/jats:italic><jats:sup>KO<\/jats:sup> tumors is associated with reduced <jats:italic>Mitf<\/jats:italic> signaling, higher translation of G2\/M proteins, and impaired guanylyl cyclase activity. Conversely, in <jats:italic>Opn4<\/jats:italic><jats:sup>WT<\/jats:sup> tumors increased small GTPase and an immune-suppressive TME are found. 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