A Targetable Developmental Program Coregulates Angiogenesis and Immune Evasion in Melanoma

Ultraviolet-induced DNA mutations generate genetic drivers of cutaneous melanoma and numerous neoantigens that can trigger antitumor immunity. Melanoma cells must therefore rapidly evade immune detection by modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Although angiogenesis typically facilitates immune infiltration, solid tumors increase vascularization while limiting immune cell entry. By comparing transcription factor (TF) expression across early-stage melanoma, nevi, and other cancers, we found that the homeodomain TF HOXD13 drives a melanoblast-like program upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we show that HOXD13 promotes tumor growth by enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D enhancer-promoter contacts activating VEGFA, SEMA3A, and NT5E (CD73), which remodel vasculature and elevate immunosuppressive adenosine. Consistently, HOXD13-induced tumor growth is reversed by combined VEGFR and adenosine receptor (AdR) inhibition, revealing a dual proangiogenic and immunosuppressive HOXD13 axis with therapeutic relevance. SIGNIFICANCE: Immune evasion contributes to cancer progression and poor response to immunotherapy. We report a novel epigenetic mechanism led by the TF HOXD13, allowing melanoma cells to simultaneously inhibit and exclude T cells, which can be counteracted therapeutically using VEGF and AdR inhibitors.