Melanoma shows heterogeneity across body sites like skin, acral skin, and the uvea, driven by molecular characteristics and genetic variations. However, comparative studies exploring the heterogeneity of melanoma across different anatomical sites remain limited, hindering a comprehensive understanding of its underlying biology. We proposed a research framework through bioinformatics to analyze the tumor ecosystems of cutaneous, acral, and uveal melanoma, from molecular characteristics to genetic variations at single-cell resolution. We found that oxidative phosphorylation (OXPHOS) is a critical driver of tumor cell evolution, with abnormal ribosomal gene and tumor suppressor expression observed in uveal melanoma (UM). Additionally, we screened for potential drug targets and drugs against tumor cells. In the immune microenvironment, acral melanoma (AM) and UM exhibit stronger immunosuppressive characteristics compared to cutaneous melanoma (CM). OXPHOS contributes to T cell cytotoxicity dysregulation in CM and AM, while interferon-γ is crucial in UM. Tumor cells may also induce T cell dysfunction through biological signals such as MIF-CD74 and HLA-E-NKG2A. This study offers valuable insights into melanoma heterogeneity, providing a comprehensive research framework for understanding the distinct molecular and immune characteristics of CM, AM, and UM, and potentially guiding the development of therapeutic strategies tailored to each melanoma subtype.