Single-cell RNA sequencing unveils tumor heterogeneity and immune microenvironment between subungual and plantar melanoma

Abstract Acral melanoma (AM) is a subtype of melanoma with high prevalence in East Asians. AM is characterized by greater aggressiveness and lower survival rates. However, there are still fewer studies on immune mechanisms of AM especially subungual melanoma (SM) versus non-subungual melanoma (NSM). In order to explore tumor heterogeneity and immune microenvironment in different subtypes of AM, we applied single-cell RNA sequencing to 24,789 single cells isolated from the SM and plantar melanoma (PM) patients. Aspects of tumor heterogeneity, melanocytes from PM and SM had significant differences in gene expression, CNV and pathways in which tumor-associated such as NF-kb and Wnt were involved. Regarding the immune microenvironment, PM contained more fibroblasts and T/NK cells. The EPHA3-EFNA1 axis was expressed only in cancer-associated fibroblast (CAF) and melanocytes of PM, and the TIGIT-NECTIN2 axis was expressed in both AM subtypes of T/NK cells and melanocytes. Altogether, our study helps to elucidate the tumor heterogeneity in AM subpopulations and provides potential therapeutic targets for clinical research.