Single-cell atlases afford high-resolution delineation of skin tumor microenvironments (TMEs). Leveraging a pan-cancer vascular atlas that includes melanoma, cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC), we chart angiogenic trajectories and resolve an APLN⁺ TipSI endothelial state whose prevalence associates with responsiveness to anti angiogenic therapy. Along the axis of skin tumor evolution, integrative analyses reconstruct the transition from normal skin and benign nevi to melanoma, revealing stage-contingent regulators: IRF1 upregulation consistent with immune surveillance in incipient lesions; emergence of HLA-E and NK-cell checkpoint inhibition; and MDK-centered stromal immune remodeling accompanying malignant conversion. In cSCC, MDK coordinates fibroblast immune circuit rewiring that favors initiation and recurrence, whereas in BCC MDK functions as an independent indicator of invasion depth, linking microenvironmental cues to clinical behavior. To therapeutically convert “cold” melanoma, we show that the BET inhibitor NHWD-870 combined with BCG targets the BRD4–MT1 axis, induces epigenetic reprogramming, enhances T-cell activation and recruitment, and constrains tumor growth. Taken together, the findings define multi-compartment control of the skin TME (vascular, stromal, immune), nominate mechanistic biomarkers (APLN⁺ TipSI, IRF1, HLA-E, MDK, MT1) with diagnostic and predictive utility, and provide a rationale for epigenetic immunologic combination therapy aimed at microenvironmental normalization and superior outcomes.

Xin Li, PhD, is an Associate Researcher and Master’s Supervisor, currently serving as Deputy Director of the Molecular Pathology Center at Chongqing University Three Gorges Hospital. She obtained her PhD in Bioinformatics from Harbin Medical University and completed her postdoctoral training in Dermatology at Xiangya Hospital, Central South University. Her research focuses on multi-omics analysis of the tumor microenvironment, with a particular emphasis on skin cancers. By integrating single-cell and spatial omics approaches, she systematically characterizes cellular composition, lineage dynamics, and intercellular communication within complex disease contexts. She has published studies in leading journals, including Nature. Her work has uncovered key regulatory drivers of tumor microenvironment remodeling, such as MDK, and clarified their roles in tumor progression, immune modulation, and therapeutic response. She has also contributed to the development of novel anti-cancer therapeutics and participated in the formulation of international and national expert consensus, supporting the translation of research findings into clinical applications.