In a significant breakthrough, researchers have discovered that mitochondrial DNA variants can predict resistance to immunotherapy in melanoma patients, shedding new light on personalized cancer treatment.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma, offering the hope of long – term remission for some patients. However, the effectiveness of these drugs varies greatly among individuals. Approximately 50% of patients still face the dilemma of ineffective treatment, and existing tumor markers, such as tumor mutational burden (TMB) or PD – L1 expression, have limited predictive capabilities.
A study led by Dr. Tomas Kirchhoff from the New York University Langone Health and its Perlmutter Cancer Center aimed to uncover the underlying genetic factors contributing to this variability. The research, published on June 5, 2025, in the prestigious journal Nature Medicine, analyzed blood samples from 1,225 patients participating in the CheckMate – 067 phase 3 clinical trial, which tested the use of immunotherapy drugs nivolumab and ipilimumab for metastatic melanoma.
The study found that a specific type of genetic mutation in mitochondrial DNA, known as mitochondrial haplogroup T (HG – T), was strongly associated with resistance to immunotherapy. Patients with HG – T were 3.46 times less likely to respond to checkpoint drugs, whether nivolumab alone or in combination with ipilimumab, compared to those with other mitochondrial haplogroups. HG – T was present in about 12% of metastatic melanoma patients.
Mitochondrial DNA is distinct from nuclear DNA, being inherited solely from the mother. Mitochondria, the energy – producing centers of human cells, have long been known to influence the development of immune cells. The researchers hypothesized that inherited genetic changes in mitochondrial DNA could impact the ability of immune cells to combat cancer in patients receiving checkpoint therapies.
Further analysis revealed that HG – T was an independent predictor of resistance to anti – PD – 1 treatment, showing no significant correlation with tumor characteristics such as PD – L1 expression, TMB, and interferon – γ (IFNγ) signaling. Single – cell RNA sequencing (scRNA – seq) analysis of peripheral CD8+ T cells in patients also showed that HG – T non – responders had a unique baseline immune profile, characterized by a higher proportion of early – differentiated T cells and a significant absence of terminally exhausted cells. These patients’ T cells also highly expressed genes involved in reactive oxygen species (ROS) detoxification, suggesting that HG – T may inhibit T – cell differentiation by enhancing ROS scavenging capabilities.
To validate their findings, the research team tested their results against samples from 675 metastatic melanoma patients of similar age and sex, who were treated with checkpoint inhibitors at 13 cancer centers participating in the International Germline Immuno – Oncology Melanoma Consortium (IO – GEM). The additional analysis confirmed the link between immunotherapy resistance and HG – T.
“This research fundamentally changes our understanding of mitochondrial genetics in immune response biology and personalized cancer immunotherapy,” said Dr. Kirchhoff. “It also suggests that variations in mitochondrial DNA could have implications beyond melanoma and apply to checkpoint treatments of other cancers.”
The discovery of HG – T as a predictive biomarker for immunotherapy resistance has important clinical implications. It could enable clinicians to identify patients who are less likely to benefit from current immunotherapy regimens before treatment begins, allowing for the consideration of alternative treatment combinations, such as new targeting other immune checkpoints like LAG – 3, TIGIT, and TIM – 3. This could potentially improve patient survival and reduce unnecessary exposure to toxic and ineffective treatments.
Looking ahead, the research team plans to conduct a prospective clinical trial to further assess the role of HG – T in immunotherapy outcomes and to explore the potential of mitochondrial genetics, ROS metabolism, and antitumor T – cell immunity as new treatment targets in cancer therapy.
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