A new study led by researchers at NYU Langone Health reveals that a molecule, crucial for regulating gene activity, plays a significant role in the growth of skin cancer and its ability to evade the immune system. The research, published online on January 30, 2026, in the journal Cancer Discovery, highlights the transcription factor HOXD13 as essential for the development of blood vessels that supply melanoma tumors with oxygen and nutrients.
The study found that HOXD13 not only stimulates angiogenesis—the process of forming new blood vessels—but also activates other signaling pathways that contribute to tumor growth. Key players in this process include vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73. Suppressing the activity of HOXD13 in experimental settings led to noticeable tumor shrinkage, suggesting its critical role in melanoma progression.
Additionally, the researchers observed that melanoma patients exhibiting high levels of HOXD13 had lower blood levels of cytotoxic T cells, which are vital for recognizing and destroying cancer cells. The study indicated that these T cells found it more challenging to infiltrate tumors in patients with elevated HOXD13, thereby diminishing immune response.
Pietro Berico, PhD, the study’s lead investigator and a postdoctoral research fellow at the NYU Grossman School of Medicine, stated, “Our study provides new evidence that transcription factor HOXD13 is a potent driver of melanoma growth and that it suppresses T cell activity needed to fight the disease.” This finding underscores the potential for targeting HOXD13 in therapeutic interventions.
The research also demonstrated that HOXD13 alters the tumor microenvironment, making it less conducive to immune function. It achieves this by increasing levels of the protein CD73, which elevates adenosine levels—a substance that inhibits T cell activity and prevents their entry into the tumor.
As a promising new treatment approach, Eva Hernando-Monge, PhD, the study’s senior investigator and a professor in the Department of Pathology at the NYU Grossman School of Medicine, emphasized the need for combined targeting of angiogenesis and adenosine-receptor pathways. Clinical trials are already underway to evaluate the safety and efficacy of VEGF-receptor and adenosine-receptor inhibitors for treating melanoma and other cancers.
The study’s authors plan to initiate clinical investigations on combining these inhibitors specifically for patients whose tumors display elevated levels of HOXD13. Hernando-Monge also aims to explore the potential of targeting VEGF and adenosine pathways in other cancers, including glioblastomas, sarcomas, and osteosarcomas.
To conduct this study, researchers analyzed tumors from over 200 melanoma patients across multiple countries, including the United States, Brazil, and Mexico. This broad analysis identified HOXD13 as a critical factor in melanoma progression. Additional experiments conducted in mice and human melanoma cell lines further confirmed the role of HOXD13 in driving angiogenesis and immune evasion.
Funding for this comprehensive study was provided by several grants from the National Institutes of Health, alongside support from the Melanoma Research Foundation, the Melanoma Research Alliance, and various international research bodies.
This research marks a significant advancement in understanding melanoma biology and offers hope for developing targeted therapies that could enhance immune response against this aggressive form of skin cancer. The ongoing clinical trials will be crucial in determining the practical application of these findings in treating patients with elevated HOXD13 levels.
For more detailed information, access the study at: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-1853/772176/A-targetable-developmental-program-co-regulates?searchresult=1.
