A new study has found that melanoma can use one protein, HOXD13, to grow new blood vessels while keeping cancer-fighting immune cells out.
The discovery points toward treatments that attack the tumor’s supply lines and its immune defenses at the same time.
Studying HOXD13
In tumor samples from more than 200 patients across the U.S., Brazil, and Mexico, the same hidden switch kept appearing.
Tracing that evidence, Pietro Berico, PhD, at NYU Grossman School of Medicine linked a gene-controlling protein called HOXD13, which acts like a switch that turns other genes on or off, to faster tumor growth and weaker immune attack.
Tumors with higher HOXD13 activity had more blood supply and fewer immune cells inside, a combination that helps cancer survive and spread.
That pattern suggests HOXD13 is not just present but actively shaping how melanoma grows and avoids treatment, pointing toward therapies that may need to block both effects together.
Blood vessels answer
Growing tumors need oxygen and nutrients, and HOXD13 helped melanoma build extra blood vessels to deliver both.
That process, called angiogenesis, simply means creating new blood vessels where cancer cells need fuel to keep dividing.
HOXD13 boosted signals that tell the body to grow new blood vessels, giving tumors easier access to the bloodstream.
Other signals also reshaped those vessels in ways that may make them harder for treatments to fully block.
Immune cells excluded
Patients with higher HOXD13 activity had fewer cancer-fighting T cells, the immune cells that destroy abnormal cells, circulating in their blood.
Inside the tumors, those same cells showed up less often, leaving the cancer with fewer defenses to overcome.
That pattern matters because many melanoma treatments rely on these immune cells already being in place to do their job.
“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,” Berico said.
Chemical signals from HOXD13
Beyond helping tumors grow, HOXD13 also increased a molecule called CD73, which helps produce a chemical that slows down the immune system.
That chemical, known as adenosine, can weaken nearby T cells and make it harder for them to attack cancer.
Earlier research had already linked the CD73 molecule to weaker immune responses, which makes HOXD13’s role more concerning.
When researchers turned off HOXD13 in experiments, more T cells were able to enter tumors and resume their attack.
Inside melanoma cells, HOXD13 changed which parts of DNA connect with genes that control growth and immune defense.
DNA can fold and loop, allowing distant sections to switch genes on or off when they come into contact.
HOXD13 strengthened those connections, turning on signals that support blood vessel growth and block immune activity.
That helps explain how a single protein can drive both faster tumor growth and stronger resistance to the immune system.
Blocking both routes
Testing treatments in mice showed the strongest evidence yet that this switch could be directly targeted.
One drug blocked the signals that help tumors grow new blood vessels, while another blocked the chemical signal that slows down immune cells.
Using both together slowed tumor growth more than either treatment on its own.
This combined approach points to a potential treatment strategy that targets both tumor growth and immune suppression at the same time.
Patients guide choices
For patients, the finding points toward selection, not a single new treatment for everyone with melanoma.
In 2026, federal cancer statistics estimated 112,000 new U.S. melanoma cases and 8,510 deaths.
Some patients with advanced melanoma receive immune checkpoint inhibitors (ICI), drugs that remove signals from T cells.
Tumors with high HOXD13 activity may need extra support from treatment, because fewer immune cells reach the areas where those drugs need to work.
Wider cancer clues
Other cancers may also use this same switch, even though melanoma showed the clearest pattern in this research.
Scientists now plan to study glioblastomas, a fast-growing type of brain cancer, where HOXD13 levels can also be high.
They will also look at sarcomas, which are cancers that form in muscles, bones, and other support tissues.
Among these, osteosarcomas, a type of bone cancer, will only be relevant if they show the same pattern of growth and immune evasion.
Limits still matter
Results in lab models do not mean a treatment targeting HOXD13 is ready for patients. Because HOXD13 works inside cells to control genes, it can be difficult to target safely with drugs.
Even treatments that block related pathways may cause side effects, since those same systems also support normal body functions.
Future clinical trials will need to identify which patients have high HOXD13 activity and test whether combined treatments improve outcomes.
This hidden switch now appears to coordinate how melanoma grows, avoids the immune system, and resists treatment.
Doctors cannot test for HOXD13 in routine care yet, but the finding gives researchers a clearer way to design treatments for the tumors most likely to evade current therapies.
The study is published in Cancer Discovery.
—–
Like what you read? Subscribe to our newsletter for engaging articles, exclusive content, and the latest updates.
Check us out on EarthSnap, a free app brought to you by Eric Ralls and Earth.com.
—–