27 Jun NYU Study Finds Genetic Mitochondrial Trait Confers Resistance to Checkpoint Inhibitors in Melanoma
MedicalResearch.com Interview with:
Dr. Kirchhoff
Tomas Kirchhoff, PhD (corresponding author)
Associate ProfessorLaura and Isaac Perlmutter Cancer Center
New York University School of Medicine
Robert Ferguson PhD
Senior Scientist at NYU Langone Medical Center
Kelsey Monson, PhD
Immuno-Oncology Postdoctoral Researcher
Icahn School of Medicine at Mount Sinai
MedicalResearch.com: What is the background for this study? Would you briefly explain how mitochondrial DNA differs from chromosomal DNA?
TK: Immune checkpoint blockade has changed the way we treat several cancers, including advanced melanoma. Before these therapies, the treatment options were very limited, but now more than half of patients experience significant tumor shrinkage or disease control.
KRM: Despite these advances, many patients still do not respond to treatment. One of the main challenges in cancer medicine today is to find ways to predict which patients will benefit from these therapies before treatment begins. This approach is key to personalizing care and improving outcomes.
RF: Mitochondria are small structures inside our cells that produce the energy needed for cells to function. Unlike most of our DNA, mitochondrial DNA is inherited only from the mother. Scientists can categorize this mitochondrial DNA into groups called haplogroups, based on unique variations in the genetic code. These haplogroups can provide insight into how cells produce energy and may affect a person’s health or response to cancer treatment.
MedicalResearch.com: What are the main findings?
KRM: We found that patients with metastatic melanoma who had a specific mitochondrial haplogroup called Haplogroup T (HG-T) were less likely to respond to Nivolumab-based immunotherapy treatments.
RF: When we studied these patients’ pre-treatment immune cells, we found that they had fewer of a specific type of CD8+ T-cells that are needed to fight the cancer. This was not only true when compared to patients that responded well to the treatment, but also when compared to patients without HG-T who didn’t respond.
TK: This means that patients with HG-T, a unique group that can be identified by HG-T marker before treatment, may have special immune system characteristics that affect how well the therapy works. Recognizing these differences could help us develop better, more personalized treatment plans.
MedicalResearch.com: Does the MT haplogroup T (HG-T) predict complete resistance to checkpoint therapy or earlier relapse? (In other words, would some patient still want to try immunotherapy in hopes of a brief remission from their metastatic melanoma, even if they carry the mutation?)
KRM: Patients with Haplogroup T have a lower statistical chance of responding to Nivolumab-based immunotherapy treatments, but this does not mean they never respond—only that their response rate is significantly lower than what is seen in the rest of the patient population.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
RF: While this study shows that patients with Haplogroup T tend to have poorer outcomes when treated with Nivolumab-based immunotherapy, more research is needed to find alternative treatments for this group.
TK: As new drugs become available, it’s important to consider this at-risk subgroup carefully. Given their unique immune profile, it is also possible that HG-T can be a marker of a better treatment response with these new drugs benefiting this specific group of patients.
Disclosures: KRM, RF, and TK are inventors on a patent application filed by NYU covering the findings described in the manuscript being discussed
Citation:
Monson, K.R., Ferguson, R., Handzlik, J.E. et al. Inherited mitochondrial genetics as a predictor of immune checkpoint inhibition efficacy in melanoma. Nat Med (2025). https://doi.org/10.1038/s41591-025-03699-3
https://www.nature.com/articles/s41591-025-03699-3#citeas
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Last Updated on June 27, 2025 by Marie Benz MD FAAD
