Neoadjuvant immunotherapy in melanoma: From pathologic response to response-adapted management

The management of resectable macroscopic stage III melanoma has been fundamentally transformed by the advent of neoadjuvant immunotherapy, and this approach is under active investigation in oligometastatic stage IV disease. This approach, which leverages the in-situ tumor to prime a broader and more robust anti-tumor immune response, offers distinct advantages over traditional adjuvant therapy, including the early assessment of treatment efficacy via pathologic response. Pivotal randomized trials, including SWOG S1801 and the phase III NADINA trial, have demonstrated significant improvements in event-free survival with neoadjuvant PD-1-based therapy compared to adjuvant therapy alone, establishing this approach as the new standard of care for selected patients with resectable macroscopic stage III melanoma. Pathologic response has emerged as a powerful prognostic marker for long-term survival and is being evaluated as a potential surrogate endpoint, which may enable response-adapted personalization of subsequent surgery and adjuvant therapy, thereby sparing toxicity in major responders and intensifying treatment for non-responders. Ongoing research is focused on integrating promising predictive biomarkers-including baseline tumor immune phenotype, circulating tumor DNA (ctDNA) dynamics, microbiome features, and peripheral immune subsets-to further refine patient selection; however, none of these biomarkers has yet been prospectively validated to direct treatment selection, de‑escalation, or escalation in routine practice. This review summarizes the current landscape of neoadjuvant immunotherapy for resectable macroscopic stage III melanoma and its investigational role in oligometastatic stage IV disease, highlighting the evidence supporting its adoption, comparing therapeutic regimens, and exploring future directions, including biomarker-informed strategies under prospective validation and the evaluation of novel combination strategies.