Immunotherapy has offered new hope to patients with pleural mesothelioma, a rare and aggressive cancer affecting the lining of the lungs. But while some patients respond well to these cutting-edge treatments, many others do not, and survival rates remain poor. Now, groundbreaking research published in Nature Genetics reveals a key factor that may determine who benefits from immunotherapy: DNA methylation. [1]
Cracking the Mesothelioma Code
Pleural mesothelioma strikes about 3,000 Americans each year, mainly due to asbestos exposure, and is often diagnosed at an advanced stage. Even with modern therapies, including immune checkpoint inhibitors (ICIs) like CTLA-4 and PD-1 blockers, the prognosis has been grim—typically just one to two years after diagnosis.
Michele Ceccarelli, Ph.D., a computational oncology researcher at the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, set out to solve a critical mystery: Why does immunotherapy work for only a subset of patients?
Beyond Standard Biomarkers
The study analyzed tumor samples from 91 patients with pleural mesothelioma treated with immunotherapy across multiple centers. Researchers first assessed tumor mutational burden—how many mutations are present in each tumor—a standard biomarker often used to predict immunotherapy response.
“We expected standard biomarkers to help guide treatment, but they did not,” explained Teresa Maria Rosaria Noviello, Ph.D, MS, a co-author and Sylvester researcher.
“That pushed us to look at the tumor in a different way,” she added.
DNA Methylation Emerges as a Predictor
Turning to DNA methylation—a process that determines whether genes are turned on or off—the team discovered a breakthrough. By grouping tumors by methylation patterns, they identified four distinct subsets, ranging from low to very high methylation.
These methylation groups closely predicted patients’ responses and survival:
Tissue and gene analyses revealed why: tumors with low methylation were rich in immune cells, making them more visible to the immune system and responsive to immunotherapy. Conversely, highly methylated tumors had fewer immune cells, rendering them invisible to immune defenses.
“Each layer of information—mutations, gene activity, immune cells—can look separate, but when you put them together, you start to see the full picture,” Dr. Noviello said. “These features can make some tumors more visible to the immune system, while others remain hidden, and that difference can shape how well immunotherapy works.”
A New Tool for Treatment Decisions
Building on these findings, the research team developed a web-based tool that enables clinicians to classify tumors by their methylation patterns, thereby estimating the likelihood of a positive immunotherapy response. While methylation testing is not yet routine in clinical practice, similar tests exist and could be adapted to focus on the specific regions identified in this study.
“The goal is to make this information usable in practice. We want clinicians to better estimate whether a patient is likely to respond,” Ceccarelli said, emphasizing the practical implications.
Toward Less Invasive Testing and New Therapies
Excitingly, the team also found that these methylation signals could be detected in blood samples, suggesting a future where less invasive liquid biopsies could guide treatment.
The findings also suggest new therapeutic strategies. Highly methylated, immune-resistant tumors may be “unmasked” using drugs called DNA demethylating agents, potentially making them more responsive to immunotherapy.
“If a tumor is not responding, we may be able to change that,” Noviello said.
“Combining immunotherapy with drugs that alter methylation could make these tumors more visible,” she noted.
Next Steps
While these results are promising, the researchers caution that the study included a relatively small number of patients, and larger studies are needed to validate the findings. The next phase will involve expanding the research to other cancer types and testing new drug combinations in clinical trials.
“This kind of work depends on integrating different types of data and working closely with clinicians,” Ceccarelli said.
“The collaborative environment at Sylvester supports this type of integrative research, helping us take meaningful steps forward in a very challenging disease,” he concluded.
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Reference
[1] Calabrò L, Caruso FP, Covre A, Noviello TMR, Lofiego MF, Tufano R, Ferraro L, Grisolia P, De Falco A, Lagano V, Sgambelluri F, Sabella G, Rossi G, Gibilisco G, Marzani F, Bello E, Simonetti E, D’Alonzo V, Caraglia M, Coral S, De Angelis A, Cerbone L, Delfanti S, Giannarelli D, Grosso F, Di Giacomo AM, Milione M, Mortarini R, Anichini A, Ceccarelli M, Maio M. Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO study. Nat Genet. 2026 Apr 27. doi: 10.1038/s41588-026-02580-4. Epub ahead of print. PMID: 42045690.
Featured image: Michele Ceccarelli, Ph.D.’s New research points to DNA methylation as a key factor in predicting who may respond to treatment. Photo courtesy: © 2026 Sylvester Comprehensive Cancer Center. Used with permission.
DOI
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Why Immunotherapy Works for Some Mesothelioma Patients but Not Others: New Research Highlights the Role of DNA Methylation – Onco'Zine
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