A new study in Cancer has uncovered a surprising vulnerability in melanoma, the deadliest form of skin cancer: its dependence on mitochondrial function. The findings, led by Jeovanis Gil, PhD, and colleagues at Lund University, suggest that this weakness can be exploited using existing drugs—particularly certain antibiotics and mitochondrial energy inhibitors—offering a promising new therapeutic approach for hard-to-treat and aggressive melanomas.
“For decades, the dogma has been that cancer cells rely mainly on glycolysis to generate energy,” said Gil. “But when we looked closely at melanoma, we kept seeing something different—tumor cells that were clearly relying on mitochondria. That was unexpected, and we realized it might be more than a quirk. It could be a vulnerability.”
Rewriting the energy playbook
Mitochondria are best known for their role in producing energy through oxidative phosphorylation (OXPHOS). They also contain their own DNA and specialized machinery for protein synthesis—machinery that closely resembles that of bacteria.
Using mass spectrometry-based proteomics, Gil’s team analyzed 151 human melanoma samples from both primary and metastatic tumors, as well as normal skin. The results were striking: aggressive melanomas showed significant upregulation in two major mitochondrial pathways—protein synthesis (mitochondrial translation) and energy production via OXPHOS.
“The more aggressive the tumor, the more these mitochondrial pathways were ramped up,” he said. “It wasn’t a subtle signal. It was consistent across different tumor types and patient samples.”
Targeting the tumor’s power supply
With this mitochondrial overactivity identified, the team next asked whether it could be therapeutically targeted. They turned to two groups of drugs: energy inhibitors that block OXPHOS (VLX600, IACS-010759, and BAY 87-2243), and a set of antibiotics—doxycycline, tigecycline, and azithromycin—that are known to interfere with bacterial protein synthesis. Because mitochondrial ribosomes are evolutionarily similar to those of bacteria, the researchers hypothesized that these antibiotics might also inhibit mitochondrial translation.
In a series of experiments, the drugs were tested on melanoma cell lines and noncancerous skin cells. The results were encouraging.
“We saw a dose-dependent killing effect on melanoma cells, while the non-cancerous cells were much more resistant,” Gil explained. “That’s the kind of therapeutic window you want to see—where you can harm the cancer but spare healthy tissue.”
A shortcut to the clinic
Importantly, all three antibiotics tested are already approved for clinical use. That opens the door to repurposing them as anti-melanoma agents—a significantly faster route to the clinic compared to developing entirely new drugs.
“Of course, you can design drugs from scratch, but that takes years,” Gil said. “We’re excited because we may already have effective tools in our hands. Repurposing drugs means we can potentially help patients sooner.”
Biomarkers and precision medicine
The study’s findings also have diagnostic potential. The researchers found that mitochondrial activity signatures could be measured in standard biopsy material, suggesting they could serve as biomarkers for identifying patients likely to benefit from mitochondrial-targeted therapies.
“This isn’t just about treatment. It’s also about stratifying patients—getting the right therapy to the right person,” Gil noted.
Implications beyond melanoma
Although the study focuses on melanoma, the broader implications are significant. Mitochondrial dysregulation is a hallmark of many types of cancer, and the strategy of targeting mitochondrial translation and energy production may apply well beyond skin cancer.
“Cancer cells are often metabolically reprogrammed,” Gil-Valdes said. “They need a lot of energy and biosynthetic capacity to grow and resist treatment. If they’re depending heavily on their mitochondria, that gives us a new angle of attack—not just for melanoma, but potentially for other cancers too.”
The immune connection
The study also uncovered links between mitochondrial activity and immune evasion. Tumors with high OXPHOS activity showed reduced expression of immune-related proteins, suggesting that targeting mitochondria could make tumors more susceptible to immunotherapies.
“That’s something we’re very interested in exploring further,” said Gil. “There may be synergy between mitochondrial inhibitors and immune checkpoint blockade, which could be particularly powerful in treatment-resistant cancers.”
The authors believe that future studies should include spatial and single-cell proteomics to better understand how these pathways behave in different tumor microenvironments, as well as clinical trials to test combination therapies.
“We’ve done the lab work and confirmed this is real,” he said. “Now we need to take it to the clinic and test these drugs in patients, ideally in combination with existing treatments like BRAF inhibitors or immunotherapy.”
