NEW YORK– A groundbreaking study led by researchers at NYU Langone Health has identified a genetic trait that may predict resistance to immunotherapy in patients with metastatic melanoma, the deadliest form of skin cancer. Published today in Nature Medicine, the findings could reshape how clinicians determine which patients are most likely to benefit from immune checkpoint inhibitors—life-extending drugs that don’t work for nearly half of those who receive them.
The study analyzed blood samples from 1,225 patients participating in the international CheckMate-067 clinical trial, which tested immunotherapy drugs like nivolumab and ipilimumab. Researchers discovered that patients with a specific inherited mitochondrial DNA variant, known as MT haplogroup T (HG-T), were 3.46 times less likely to respond to immunotherapy than those without the trait.
“This is the first time we’ve been able to link a genetic biomarker to poor response to checkpoint immunotherapy in metastatic melanoma,” said co-lead investigator Dr. Robert Ferguson, a molecular biologist at NYU Grossman School of Medicine. “Identifying this mitochondrial mutation offers a potential tool to guide treatment decisions and improve patient outcomes.”
Mitochondrial DNA, which is passed exclusively from mothers to their offspring, was a focus of the study due to its previously suspected role in immune system function. Researchers found that the HG-T variant altered the development of T cells, key players in the body’s immune response. Patients with HG-T had more underdeveloped T cells and greater resistance to reactive oxygen species—chemicals that help trigger immune attacks on cancer cells—blunting the effectiveness of immunotherapy.
To validate the results, the researchers analyzed an additional 397 melanoma cases from NYU Langone’s database as part of the International Germline Immuno-Oncology Melanoma Consortium (IO-GEM). Again, the presence of HG-T strongly correlated with resistance to immunotherapy.
Dr. Kelsey Monson, co-lead investigator and epidemiologist at NYU Langone, emphasized the clinical significance: “Checkpoint immunotherapy is a cornerstone of modern cancer care, but its variable effectiveness has remained poorly understood. Our results offer a clearer explanation for that variability and point to a new direction for patient-specific cancer treatment.”
The drugs used in the study, developed by Bristol Myers Squibb—which also sponsored the trial—help the immune system recognize and attack cancer cells by disabling the tumor’s ability to hide using “checkpoints” on T cells. While effective in many cases, the therapy fails in about half of metastatic melanoma patients, underscoring the need for predictive tools like genetic screening.
Senior investigator Dr. Tomas Kirchhoff said the team now plans to launch a prospective clinical trial to test whether patients without HG-T respond more favorably to immunotherapy, and whether similar mitochondrial variants influence response in other cancers. “This opens the door to precision oncology based not just on nuclear DNA, but on mitochondrial genetics as well,” Kirchhoff said.
The research was funded by the National Institutes of Health and supported by additional grants from the Melanoma Research Alliance and international partners. Investigators from more than a dozen institutions across the United States and Europe collaborated on the study.
