Circulating Tumor DNA in Melanoma: Advances in Detection, Clinical Applications, and Integration with Emerging Technologies

Circulating tumor DNA (ctDNA) has gained increasing attention as a non-invasive biomarker with potential utility across multiple stages of melanoma. ctDNA reflects tumor-derived genetic alterations in real time and has shown value in detecting minimal residual disease, identifying early recurrence, estimating tumor burden, and monitoring response to systemic therapies. In early-stage melanoma, postoperative ctDNA positivity is strongly associated with higher recurrence risk and often precedes radiologic detection. In advanced disease, ctDNA correlates with tumor volume and can distinguish responders from non-responders during targeted therapy and immunotherapy, while also identifying emerging resistance mechanisms. Despite these advantages, clinical implementation remains limited by low shedding in early-stage disease, variation among detection platforms, and the absence of standardized clinical thresholds. Recent advances, including fragmentomics, methylation assays, and multi-target sequencing strategies, aim to improve sensitivity, particularly in low-tumor-burden settings. Integration of ctDNA with radiomics, artificial intelligence, and digital pathology represents an additional opportunity to enhance precision in risk stratification and treatment adaptation. This review summarizes current evidence on ctDNA biology, detection methods, and clinical applications in melanoma and outlines ongoing challenges and future directions required for translation into routine practice.