From Excision to Immunity: The Full Spectrum of Modern Melanoma Treatments

Cutaneous Melanoma is a biologically heterogeneous malignancy. Although recent therapeutic advances have improved survival, durable remissions remain elusive for many patients. Surgical excision with stage-appropriate margins and selective nodal staging remains the cornerstone of curative-intent management. In contrast, conventional cytotoxic chemotherapy now plays a limited, largely palliative role given its modest efficacy and substantial toxicity. Targeted therapy with BRAF/MEK inhibitors has improved outcomes in patients with BRAF V600-mutant melanoma, resulting in rapid tumor regression and meaningful survival benefits. However, long-term disease control is frequently compromised by adaptive resistance, commonly driven by MAPK pathway reactivation or compensatory PI3K/AKT signaling. In parallel, immune checkpoint inhibitors targeting PD-1, CTLA-4, and emerging pathways have reshaped treatment across disease stages, enabling deep and sometimes durable responses. Despite this progress, primary and acquired resistance, as well as acute and chronic immune-related toxicities, continue to pose significant clinical challenges. Current therapeutic strategies focus on rational combinations of targeted therapy, checkpoint blockade, IL-2-based approaches, oncolytic viruses, and adoptive cell therapies such as tumor-infiltrating lymphocytes to enhance response depth and durability. However, these intensified regimens carry increased toxicity risks, highlighting the need for improved patient selection and monitoring. Overall, emerging evidence supports a paradigm shift toward optimized treatment sequencing, response-adapted surgical strategies, and biomarker-guided personalization to maximize clinical benefit while minimizing toxicity.