Genetic Differences in Cell Energy Centers Predict Resistance to Skin Cancer Therapy

Results from a new study help resolve the decade-long mystery of why many patients with the deadliest form of skin cancer do not respond to the latest cancer treatments. Specifically, researchers found patients with metastatic melanoma who did not respond to immune checkpoint inhibitors had DNA with differences not found in the DNA of those who did respond. These genetic differences are both testable and predictive of who is least likely to respond to checkpoint therapies, a treatment class that has become a mainstay against the disease.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the study included a genetic analysis of blood samples from patients participating in the landmark CheckMate-067 phase 3 trial, which tested frontline use of checkpoint inhibitors to treat their metastatic melanoma.

After analyzing genetic material from 1,225 patients with metastatic melanoma, the study authors found that inherited genetic differences in mitochondrial DNA, called mitochondrial haplogroup T (HG-T), predicted resistance to checkpoint immunotherapy. Patients with HG-T were 3.46 times less likely to respond to checkpoint drugs, either nivolumab prescribed on its own or in combination with another checkpoint inhibitor, ipilimumab, than patients with other mitochondrial haplogroups. HG-T was found to be present in approximately 12 percent of metastatic melanoma patients.

The study revolved around mitochondrial haplogroups that have evolved in DNA inherited by offspring only from the mother. Mitochondrial DNA is different from so-called nuclear DNA, which is passed down from both a mother and a father. Mitochondria are part of every human cell, serving as its energy center, and have long been known to play a role in how immune cells develop.

For the study, published in the journal Nature Medicine online June 5, researchers focused on mitochondrial genetics due to recent evidence suggesting that these cell powerhouses are essential for immune cell function. The scientists hypothesized that inherited genetic changes in mitochondrial DNA might affect immune cells’ ability to fight cancer in patients treated by checkpoint therapies.

These drugs work by blocking the interaction of cancer cells with checkpoint proteins, molecules that sit on the surface of immune T cells and are important in switching off the immune response to avoid attack on friendly, healthy cells. By blocking checkpoint interactions, these immune inhibitor drugs prevent T cells from becoming inactivated, enabling them to continue attacking cancer cells.

While both drug regimens, nivolumab alone or combined with ipilimumab, proved effective in more than 50 percent of all incoming treated patients, results from the new analysis showed that this positive response to treatment declined to 18 percent in patients with HG-T, who are largely resistant to each of these otherwise beneficial therapies.

To validate their findings from CheckMate-067, researchers tested their initial results against samples from 675 metastatic melanoma patients of similar age and the same sex who were treated by checkpoint inhibitors at any of 13 cancer centers participating in the International Germline Immuno-Oncology Melanoma Consortium (IO-GEM), including NYU Langone’s Interdisciplinary Melanoma Cooperative Group (IMCG). Results from this additional analysis confirmed the same link of immunotherapy resistance to HG-T.

“This research fundamentally changes our understanding of mitochondrial genetics in immune response biology and personalized cancer immunotherapy,” said senior study investigator Tomas Kirchhoff, PhD. “It also suggests that variations in mitochondrial DNA could have impact beyond melanoma and apply to checkpoint treatments of other cancers.” Dr. Kirchhoff is an associate professor in the Department of Population Health at NYU Grossman School of Medicine, a member of the Perlmutter Cancer Center, and leader of the IO-GEM.

“Our study offers the first scientific evidence of an inherited genetic marker, the presence of mitochondrial haplogroup T, as a means of identifying those metastatic melanoma patients who are least likely to respond to immunotherapy treatment,” said study co-lead investigator and epidemiologist Kelsey Monson, PhD.

“Our findings make possible the clinical testing for the presence of mitochondrial haplogroup T to determine nonresponding patients before they start immunotherapy, so other treatment combinations can be considered,” said study co-lead investigator and molecular biologist Robert Ferguson, PhD, who like Dr. Monson is a member of Kirchhoff Lab. “This in turn could improve patient survival.”

“These study results also raise the possibility that other mitochondrial haplogroup variants could influence which patients respond to other immune checkpoint therapies, allowing us to use this biomarker to personalize treatment prediction to a larger patient population,” said Dr. Kirchhoff.

Among the study’s other key findings was that treatment-resistant HG-T patients had more underdeveloped T cells in their blood than nonresistant patients without HG-T. The researchers traced this poor differentiation to increased resilience to reactive oxygen species (ROS), toxic chemicals primarily produced by mitochondria. This suggests that HG-T conferred some form of ROS protection that stunted the T cell attack against tumors.

Dr. Kirchhoff says this study opens new future research avenues to determine the precise role played by mitochondrial genetics, ROS metabolism, and antitumor T cell immunity in cancer therapy. The more immediate next step is a prospective clinical trial to assess whether non-HG-T patients fare better on immunotherapy than patients with HG-T, and whether this applies to other mitochondrial haplogroups and other cancers.

Funding for the study was provided by National Institutes of Health grants R01CA227505, F99CA274650, P50CA225450, and P30CA008748, with additional support from Melanoma Research Alliance grant MRA-686192 and Italian Ministry of Health Ricerca Corrente grants M2/2 and L1-2.

Both drugs used in the CheckMate trial are manufactured by pharmaceutical company Bristol Myers Squibb, which sponsored the trial and provided the patient specimens and data used in the analysis. The CheckMate trial involved more than 100 medical centers in 19 countries. The IO-GEM is the largest repository of genetic information from melanoma patients treated with “standard-of-care” immunotherapy (treatment outside of a clinical trial). NYU Langone’s Interdisciplinary Melanoma Cooperative Group contributed nearly 200 blood samples for the study.

Reference: Monson KR, Ferguson R, Handzlik JE, et al. Inherited mitochondrial genetics as a predictor of immune checkpoint inhibition efficacy in melanoma. Nat Med. 2025. doi: 10.1038/s41591-025-03699-3

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