SignificanceWe present new approaches to treat both primary cutaneous and ocular melanoma, with potential to reduce metastatic spread ApproachIn mouse models optical clearing combined with dual-photosensitizer PDT is used to treat primary cutaneous xenogafts. Two-photon PDT is used in ocular melanoma of extraocular (conjunctival) or intraocular (uveal) melanoma. Immune effects are investigated in immunocompetent mice using blood biomarkers and by tumor re-challenge. In vitro studies in pigmented and non-pigmented melanoma cells show melanin-mediated photosensitization as a novel mechanism of action of 2-γ PDT. ResultsFull-thickness primary tumor eradication has been achieved: ∼1 and 4 mm in immune deficient and competent mice, respectively. Marked reduction in metastatic tumor burden is observed in the latter. ConclusionsThese studies reopen the possibility of PDT as an effective modality in melanoma.