Melanoma has been the proving ground for modern oncology, with checkpoint inhibitor immunotherapy and BRAF-targeted therapy first established here before transforming the treatment of many other cancers. Now, mRNA-based individualised neoantigen therapy is poised to do the same. Yet a significant proportion of patients with melanoma, the "third space", do not have durable cancer control and relapse or progress despite systemic therapy. Using clinical, tissue and on-treatment biomarkers, those predicted to be resistant can be identified early in their cancer journey and offered novel experimental therapies upfront, rather than after standard treatment fails. The neoadjuvant platform provides a framework to test these strategies efficiently, leaving room for further novel therapies should patients progress or recur. The blueprint established in melanoma has the potential to shape the whole field of oncology.