Melanoma of unknown primary: a comprehensive review of immune-mediated pathogenesis and therapies

Melanoma of unknown primary (MUP) is a rare subtype of melanoma, with its low incidence posing challenges for clinical management. This systematic review integrates recent advances in MUP research, with a focus on pathogenesis, molecular characteristics, and therapeutic strategies. The proposed pathogenesis involves spontaneous regression of the primary lesion, potentially driven by sequential immune responses mediated by T cells and natural killer cells. At the molecular level, whole-exome/genome analyses reveal that MUP and cutaneous melanoma share a highly concordant UV damage-driven mutational landscape; nevertheless, MUP exhibits distinct genomic alterations, including recurrent mutations in the telomerase reverse transcriptase promoter, protein phosphatase 6 catalytic subunit, and isocitrate dehydrogenase 1. Current therapeutic approaches are similar to those for advanced melanoma, encompassing surgery, immune checkpoint inhibitors (ICIs), and targeted therapies. While ICIs have demonstrated significant improvements in survival, the clinical efficacy of targeted therapies in MUP remains to be fully established. By consolidating current knowledge, this review provides insights to guide diagnosis, treatment, and future research in MUP.