Researchers at NYU Langone Health and its Perlmutter Cancer Center have discovered that a gene-regulating molecule called HOXD13 plays a powerful role in helping melanoma grow and evade the body’s immune defenses.
Their findings, published in the journal Cancer Discovery, could open the door to new treatment strategies for this dangerous form of skin cancer.
Melanoma is an aggressive type of skin cancer that can spread quickly if not treated early. For tumors to grow, they need a steady supply of oxygen and nutrients.
One way they achieve this is by forming new blood vessels, a process known as angiogenesis. The new study shows that HOXD13 is a major driver of this process.
HOXD13 is a transcription factor, meaning it helps control how genes are turned on or off inside cells.
The researchers found that high levels of HOXD13 increased the activity of several signaling pathways involved in blood vessel formation, including those linked to vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73. When scientists blocked HOXD13 in laboratory experiments, melanoma tumors shrank.
But HOXD13 does more than promote blood vessel growth. The study also revealed that it helps tumors escape the immune system. Normally, cytotoxic T cells patrol the body and destroy cancer cells.
However, in melanoma patients with high HOXD13 activity, blood levels of these cancer-fighting T cells were lower. Even when T cells were present, their ability to enter tumors was reduced.
Further investigation showed how this immune evasion works. HOXD13 increases levels of a protein called CD73. CD73 boosts production of adenosine, a molecule that dampens immune responses. Adenosine acts like a protective shield around the tumor, slowing down T cells and preventing them from attacking cancer cells effectively. When HOXD13 was turned off in experimental models, more T cells were able to enter the tumors, improving the immune response.
The researchers analyzed tumor samples from more than 200 melanoma patients in the United States, Brazil, and Mexico. HOXD13 stood out as one of the most active pathways in aggressive tumors. Additional experiments in mice and human melanoma cells confirmed that HOXD13 drives both blood vessel growth and immune suppression.
The findings suggest that targeting HOXD13-related pathways could be a promising treatment approach. Some clinical trials are already testing drugs that block VEGF receptors or adenosine receptors in melanoma and other cancers. In some cases, these drugs are being combined with immunotherapy treatments. The research team hopes that combining inhibitors of both VEGF and adenosine pathways may be especially effective in patients whose tumors show high HOXD13 levels.
Scientists also plan to explore whether HOXD13 plays a similar role in other cancers, including certain brain tumors and bone cancers.
By uncovering how HOXD13 fuels tumor growth and weakens immune defenses, this research provides a clearer picture of melanoma’s biology and points toward more targeted, personalized therapies in the future.
