Canine Oral Melanoma as a Translational Model for Human Mucosal Melanoma: Molecular Architecture, Immune Landscape, and Therapeutic Implications

ABSTRACT

Human mucosal melanoma (hMM) is a rare but highly aggressive malignancy with poor clinical outcomes and limited responsiveness to current immunotherapeutic strategies. Unlike cutaneous melanoma, hMM is characterized by an ultraviolet‐independent pathogenesis, low tumour mutational burden, and pronounced molecular and immunological heterogeneity, which collectively inhibit effective translational modelling and therapeutic development. Naturally occurring canine oral melanoma (cOM) shares key biological features with hMM, including spontaneous tumour development in immunocompetent hosts, low mutational burden, extensive structural genomic alterations, and a highly immunosuppressive tumour microenvironment. These shared characteristics support the positioning of cOM as a relevant comparative oncology model for investigating the mechanisms underlying tumour aggressiveness, immune evasion, and therapeutic resistance in mucosal melanoma. In this review, we synthesize evidence suggesting that hMM and cOM are driven less by single dominant oncogenic mutations than by a complex convergence of pathway‐level dysregulation arising from pervasive copy‐number alterations, structural variants, and epigenetic plasticity. We further highlight the influence of these molecular features on immune visibility and immune suppression, as well as their contributions to the limited efficacy of single‐agent targeted therapies and immune checkpoint blockade. Insights from canine immunotherapy studies provide preliminary translational support for combination‐based therapeutic strategies and biomarker development. By integrating molecular, epigenetic, and immunological perspectives across species, this review supports the use of cOM as a comparative and translational platform for advancing therapeutic innovation in mucosal melanoma.