AbstractThe search for new therapeutical targets for cutaneous melanoma and other cancers is an ongoing task. 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 Opn4, compared to Opn4^WT due to an impaired cell cycle progression and reduced melanocyte inducing transcription factor (Mitf) expression. In vivo tumor progression of Opn4^KO cells is remarkably reduced due to slower proliferation, and higher immune system response in Opn4^KO tumors. Using pharmacological assays, we demonstrate that guanylyl cyclase activity is impaired in Opn4^KO cells. Evaluation of Tumor Cancer Genome Atlas (TCGA) database confirms our experimental data as reduced MITF and OPN4 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 Opn4^KO tumors is associated with reduced Mitf signaling, higher translation of G2/M proteins, and impaired guanylyl cyclase activity. Conversely, in Opn4^WT tumors increased small GTPase and an immune-suppressive TME are found. Such evidence points to OPN4 as an oncogene in melanoma, which could be pharmacologically targeted.