Acral melanoma: a unique subtype requiring unique solutions

Acral melanoma (AM) is a 'rare-by-rare' melanoma subtype arising on the volar skin of the palms, soles, or nail apparatus. Unlike sun-exposed cutaneous melanoma (CM), AM has a low mutational burden but extensive structural genomic alterations, including clustered copy number events ('hailstorms'/tyfonas) that contain amplification of oncogenes such as CCND1 and TERT. Mechanical stress and distinct clonal evolution, with late, often subclonal, MAPK mutations, may mediate AM development and progression. Nevertheless, AM management is largely extrapolated from CM. Benefits of immunotherapy and targeted therapies remain unclear due to limited trial enrollment and under-representation of diverse patient populations. In this review, we integrate current knowledge with critical challenges in AM research and outline priorities to accelerate AM-specific discoveries and treatments, close critical knowledge gaps, and improve patient outcomes through global collaboration.