The article "PRAME Updated: Diagnostic, Prognostic, and Therapeutic Role in Skin Cancer" by Fortunato Cassalia et al. provides an in-depth review of the role of Preferentially Expressed Antigen in Melanoma (PRAME) in skin cancer diagnostics, prognosis, and therapy. PRAME, a member of the cancer/testis antigen family, is a nuclear receptor and transcriptional regulator that plays a critical role in inhibiting retinoic acid signaling, which is essential for cell differentiation and proliferation. Its overexpression in various malignancies, particularly cutaneous melanoma, is associated with more aggressive tumor phenotypes, making it a valuable diagnostic and prognostic marker. The article highlights the diagnostic value of PRAME in various skin lesions, including uveal melanoma, acral melanomas, and non-melanoma skin cancers (NMSCs). PRAME is highly expressed in melanomas but weak or absent in benign nevi, improving the accuracy of differential diagnoses. In uveal melanoma, PRAME expression correlates with an increased risk of metastasis. In acral melanomas, PRAME helps improve diagnostic accuracy, especially in cases with histopathological ambiguity. However, its expression in spitzoid and unguial melanocytic lesions is inconsistent and requires a comprehensive approach for accurate assessment. PRAME's potential as a therapeutic target is also discussed. Emerging immunotherapies, including T-cell-based therapies and vaccines targeting PRAME, are being investigated to exploit its cancer-specific expression. The article emphasizes the ongoing research into the molecular role and mechanism of action of PRAME in skin cancer, which continues to open new avenues in both diagnostics and therapeutics, with the potential to transform the management of melanoma and related skin cancers.The article "PRAME Updated: Diagnostic, Prognostic, and Therapeutic Role in Skin Cancer" by Fortunato Cassalia et al. provides an in-depth review of the role of Preferentially Expressed Antigen in Melanoma (PRAME) in skin cancer diagnostics, prognosis, and therapy. PRAME, a member of the cancer/testis antigen family, is a nuclear receptor and transcriptional regulator that plays a critical role in inhibiting retinoic acid signaling, which is essential for cell differentiation and proliferation. Its overexpression in various malignancies, particularly cutaneous melanoma, is associated with more aggressive tumor phenotypes, making it a valuable diagnostic and prognostic marker. The article highlights the diagnostic value of PRAME in various skin lesions, including uveal melanoma, acral melanomas, and non-melanoma skin cancers (NMSCs). PRAME is highly expressed in melanomas but weak or absent in benign nevi, improving the accuracy of differential diagnoses. In uveal melanoma, PRAME expression correlates with an increased risk of metastasis. In acral melanomas, PRAME helps improve diagnostic accuracy, especially in cases with histopathological ambiguity. However, its expression in spitzoid and unguial melanocytic lesions is inconsistent and requires a comprehensive approach for accurate assessment. PRAME's potential as a therapeutic target is also discussed. Emerging immunotherapies, including T-cell-based therapies and vaccines targeting PRAME, are being investigated to exploit its cancer-specific expression. The article emphasizes the ongoing research into the molecular role and mechanism of action of PRAME in skin cancer, which continues to open new avenues in both diagnostics and therapeutics, with the potential to transform the management of melanoma and related skin cancers.