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.

Dr. Mingzhu Yin, MD, PhD, is Professor and Chair of the Clinical Research Center at Chongqing University Three Gorges Hospital, and leads the Medical Pathology Center, Cancer Early Detection and Treatment Center, and Translational Medicine Research Center. He received his MD in Oncology from Harbin Medical University (2008) and a PhD from China Pharmaceutical University with joint training at Yale. He trained as a postdoctoral scholar at the NIA/NIH and later served as Associate Scientist at Yale (2012–2018). Dr. Yin founded China’s first NUT carcinoma specialty and led the nation’s first expert consensus, establishing a gene-diagnosis working group. His team secured five national Class 1.1 new drug trial approvals targeting NUT carcinoma; phase Ib is completed and phase II is ongoing, with early data indicating a 2.4-fold survival improvement. He built an AI-based platform for target discovery and screening, elucidating targets such as BRD4, CECR2, and KDM5B. Dr. Yin has authored 110+ publications and holds 20 patents; his work is supported by NSFC, NKPs, and provincial agencies. He is Editor-in-Chief of Tumor Discovery and holds leadership roles in CAST, FDSA, CACA, and SAPA.