A targetable developmental program co-regulates angiogenesis and immune evasion in melanoma
Ultraviolet (UV)-induced DNA mutations generate genetic drivers of cutaneous melanoma and numerous neoantigens that can trigger anti-tumor 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, naevi, 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 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 pro-angiogenic and immunosuppressive HOXD13 axis with therapeutic relevance.
Authors
- Ines Delclaux (ORCID: https://orcid.org/0009-0001-6420-2934)
- Ata S. Moshiri (ORCID: https://orcid.org/0000-0001-6684-4503)
- Michelle Krogsgaard (ORCID: https://orcid.org/0000-0001-5006-7981)
- Miguel João Costa (ORCID: https://orcid.org/0000-0002-2015-6059)
- Martha Estefania Vázquez‐Cruz (ORCID: https://orcid.org/0009-0007-7111-109X)
- Irving Simonin Wilmer (ORCID: https://orcid.org/0000-0002-6298-2359)
- Tara Muijlwijk (ORCID: https://orcid.org/0000-0003-3827-5694)
- Patrícia A. Possik (ORCID: https://orcid.org/0000-0003-2899-0969)
- Amanda W. Lund (ORCID: https://orcid.org/0000-0001-7389-9983)
- Jane A. Skok (ORCID: https://orcid.org/0000-0002-4145-1516)
- Pietro Berico (ORCID: https://orcid.org/0000-0001-8034-0790)
- Catherine Do (ORCID: https://orcid.org/0000-0002-9796-4345)
- Carla Daniela Robles Espinoza
- Iman Osman
- Eva Hernando
- Amanda Flores Yanke (ORCID: https://orcid.org/0000-0002-1365-2695)
- Robert Stagnitta
- Fatemeh Vand-Rajabpour (ORCID: https://orcid.org/0000-0002-5833-6071)
- Markus Schober
- Theodore Sakellaropoulos
- Annie Cristhine Moraes Sousa-Squiavinato
Institutions
- Autonomous University of Queretaro (MX)
- NYU Langone Health (US)
- Instituto Nacional de Câncer - INCA (BR)
- Instituto Nacional del Cáncer (CL)
- New York University (US)
- Universidad Nacional Autónoma de México (MX)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-02-03
- DOI
- https://doi.org/10.1158/2159-8290.cd-24-1853
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00