Abstract

Mucosal melanoma (MM), an aggressive melanoma subtype arising in mucosal tissues, displays resistance to therapies effective in cutaneous melanoma. To understand how mucosal microenvironment contributes to treatment nonresponsiveness, we performed integrative analysis of single-cell and bulk messenger RNA sequencing data derived from oral mucosa–originated melanoma and revealed that mucosa-specific inflammation induces enrichment of low-pigmented neural crest–like cancer cell, mediated by COX2 + macrophages and their secretome. Maintenance of this inflammation-induced neural crest–like state in cancer cells depends on HER2 and HER3 activation. Inhibition of HER2/3 by pan-HER inhibitors blocks cell state plasticity and overcomes chemoresistance in primary MM cell lines and patient-derived xenograft (PDX) models. These findings provide insights into how the tissue of origin determines cancer aggressiveness, highlight the role of mucosal inflammation in driving melanoma stemness and chemoresistance, and advance the identification of effective treatment options currently lacking for patients with MM.