A site-specific microenvironmental program in plantar skin confers heightened metastatic capacity to acral melanomas

Acral melanoma is an aggressive melanoma subtype with a predilection for metastasis and poor clinical outcomes, yet no FDA-approved therapies are tailored specifically for this population. Progress has been hindered by limited clinico-genomic data and a lack of orthotopic preclinical models. Here, we integrate genomic profiling and longitudinal clinical annotations from 29 patients with metastatic acral melanoma-alongside a comparison cohort of 455 patients with cutaneous melanoma-revealing an enhanced metastatic capacity in acral disease. We further show that the plantar skin microenvironment fosters a human acral melanoma, pro-metastatic cell state through elevated matrix stiffness, and identify a matrix stiffness-induced FAK-SRC-YAP vulnerability as a therapeutically actionable axis to combat distant metastasis. This work establishes the first series of orthotopic models of metastatic acral melanoma and uncovers tractable drivers of distant organ metastasis, offering new avenues for tailored therapeutic strategies.