Scientists have identified a key molecular “master switch” that not only fuels the growth of melanoma — the deadliest form of skin cancer — but also helps tumors hide from the body’s own immune defenses. The discovery, led by researchers at NYU Langone Health and its Perlmutter Cancer Center, could open the door to new combination treatments for patients who don’t respond to current therapies.
The study, published in the journal Cancer Discovery, centers on a protein called HOXD13 — a type of molecule known as a transcription factor. Transcription factors act like switches inside cells, controlling how genetic instructions stored in DNA are turned into the proteins the body needs. In this case, HOXD13 appears to be hijacked by melanoma to power tumor growth and avoid immune attack.
A Protein That Feeds Tumors
One of the key ways HOXD13 drives melanoma is by fueling blood vessel growth — a process called angiogenesis. Tumors need a steady supply of oxygen and nutrients to grow, and HOXD13 activates several biological pathways that help build those supply lines.
These pathways include ones involving proteins called VEGF (vascular endothelial growth factor), SEMA3A (semaphorin-3A), and CD73. When researchers reduced HOXD13 activity in laboratory experiments, tumors shrank in size — a clear sign that this protein plays a central role in keeping cancer cells alive and multiplying.
How Melanoma Hides from the Immune System
Perhaps the most striking finding is how HOXD13 also shields tumors from immune attack. The body relies on specialized cells called cytotoxic T cells to seek out and destroy cancer cells. But the study found that melanoma patients with high levels of HOXD13 had notably fewer of these T cells circulating in their blood, and those T cells had a harder time entering tumors.
The mechanism behind this immune evasion involves CD73, one of the proteins activated by HOXD13. CD73 raises levels of a substance called adenosine, which acts as a chemical barrier around the tumor. Adenosine essentially puts the brakes on T cells, slowing them down and stopping them from penetrating cancerous tissue. When researchers switched off HOXD13 in experiments, T cells were able to move into tumors far more effectively.
“Our study provides new evidence that transcription factor HOXD13 is a potent driver of melanoma growth and that it suppresses the T cell activity needed to fight the disease,” said Pietro Berico, PhD, the study’s lead investigator and a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center.
Tumors Analyzed Across Three Countries
To reach these conclusions, the research team analyzed tumor samples from more than 200 melanoma patients drawn from the United States, Brazil, and Mexico. Scientists examined which biological pathways were more or less active across these tumors, and HOXD13 consistently stood out as a key driver.
Additional experiments in mice and human melanoma cell lines backed up those findings. Blocking HOXD13 alongside VEGF and adenosine pathways confirmed just how central this protein is to a tumor’s ability to survive and grow. The study also involved collaborators from the National Autonomous University of Mexico and the Brazilian National Cancer Institute in Rio de Janeiro.
Opening Doors to Combination Therapies
The research team believes this discovery could lead to a promising new treatment strategy. Clinical trials are already underway testing drugs that block VEGF receptors or adenosine receptors in melanoma and other cancers, and some of these trials are combining those drugs with immunotherapy — treatments that use the body’s own immune system to fight cancer.
“This data supports the combined targeting of angiogenesis and adenosine-receptor pathways as a promising new treatment approach for HOXD13-driven melanoma,” said Eva Hernando-Monge, PhD, a professor in the Department of Pathology at NYU Grossman School of Medicine and the study’s senior investigator.
If upcoming clinical trials prove successful, the team plans to test combination therapies targeting both VEGF and adenosine receptors specifically in patients with elevated HOXD13 levels. Researchers also intend to explore whether the same pathways could be targeted in other cancers where HOXD13 is elevated — including certain glioblastomas, sarcomas, and osteosarcomas.
Why This Research Matters
Melanoma is responsible for the vast majority of skin cancer deaths despite being less common than other forms of skin cancer. One of the biggest challenges in treating it is that melanoma cells can alter their gene expression to become “invisible” to the immune system, making standard immunotherapy less effective in some patients.
The identification of HOXD13 as a driver of both tumor growth and immune evasion gives researchers a specific target to focus on. Early work by Berico, funded in part by the Melanoma Research Foundation, had already suggested that HOXD13 is almost exclusively expressed in melanoma cells from patients who do not respond to immunotherapy — a finding that points to its potential as a biomarker for treatment resistance.
The study received support from the National Institutes of Health, the Melanoma Research Foundation, the Melanoma Research Alliance, the United Kingdom Medical Research Council, and Brazil’s National Council for Scientific and Technological Development.
