The dynamically evolving cell states and ecosystem from benign nevi to  melanoma
Approximately 30% of non-chronically sun-damaged melanomas originate from nevi, yet thedynamic changes and crucial mechanisms driving the transition from benign nevi tomelanoma remain elusive. Here, we performed single-cell transcriptome sequencing onmultiple paired tissue sites from 5 patients diagnosed with melanoma arising in congenitalmelanocytic nevi (CMN), identifying four distinct states of melanocyte subpopulations duringthe progression from nevi to melanoma, characterized by dynamic changes in theircomposition, functions, malignancy, and regulatory pathways. In the nevi state, interferonregulatory factor 1 (IRF1) was specifically upregulated in melanocytes, fibroblasts, andendothelial cells (ECs), potentially activating immune surveillance in the microenvironment.This underscores a critical factor in preserving the benign state of nevi and averting malignanttransformation. Conversely, the critical inhibitory checkpoint HLA-E for NK cells exhibited highexpression in a cluster of malignant melanocytes and fibroblasts enriched in melanoma. Thisinteraction with ligands expressed on NK cells could potentially serve as a key factor leadingto immune evasion. In malignant melanoma samples, we detected high expression of Midkine(MDK) in melanocytes. It is a pivotal factor that facilitates melanoma invasion and malignanttransformation, potentially through interaction with ECs to stimulate angiogenesis. The targetsidentified in our study are crucial factors in detecting the malignant transformation of nevi.Ultimately, we developed a malignant progression model capable of predicting patientprognosis and malignant progression status using bulk RNA sequencing (RNA-seq) data. Ourstudy provides a high-resolution atlas of the malignant transformation of melanoma from neviand highlights potential targets for further investigation.Overall design: In this study, we conducted single-cell transcriptome sequencing on paired tissue sites from 5 patients diagnosed with melanoma arising in congenital melanocytic nevi (CMN) to conduct a comprehensive study and offer novel insights into the malignant transformation of nevi.