A distinct subgroup with Schwann-like differentiation presents immune resistance and poor prognosis in plantar melanoma.

Background: Intratumor heterogeneity in plantar melanoma orchestrates transcriptional programs that contribute to resistance to target- and immuno-therapies. However, the evolution and spatial distribution of cellular subgroups, as well as their effects on immune environment and patient prognosis, remain unclear. Methods: We analyzed 218,021 cells from 20 plantar melanoma and 6 normal samples using single-cell RNA sequencing to reveal the evolutionary characteristics and communication patterns of tumor subgroups. Spatial transcriptomics and multiplex immunohistochemistry (mIHC) were used to map the spatial distribution of these subgroups, with mIHC scores further evaluating their correlation with patient prognosis. Single-cell multiomics analysis identified key transcription factors associated with chromatin accessibility. In addition, survival analysis was performed using bulk RNA sequencing data from 68 melanoma patients. Results: We identified a continuum of subgroups originating from stem cells via transitional and Schwann cell-like precursor states, ultimately reaching a Schwann cell-like state. This evolution trajectory was supported by integrative evidence, including assessments of stemness, transitional states, RNA velocity, and transcription factors. The histological distribution of these subgroups was validated by spatial transcriptomics and multiple IHC. Notably, Schwann cell-like subgroup, regulated by transcription factor HMGA2, was associated with immune cell dysregulation and a worse prognosis, including increased invasion and lymph node metastasis. Mechanically, inhibition of HMGA2 expression blocked the transition to Schwann-like melanoma fate. Conclusions: This study reveals the unique evolutionary trajectory of plantar melanoma, showing its differentiation towards a Schwann-like fate regulated by HMGA2, leading to a decline in pigment function, enhanced immune tolerance and an increased propensity for lymph node metastasis.