Ancestry Shapes the Side Effects of Melanoma Immunotherapy, Study Finds

Immune checkpoint inhibitors have transformed the treatment of melanoma, unleashing the body’s own immune system against tumor cells and delivering durable remissions to patients who once had few options. But these powerful drugs come with a well-known trade-off: by removing the molecular brakes on T cells, they can also trigger the immune system to attack healthy tissue, producing immune-related adverse events that range from mild rashes and thyroid dysfunction to life-threatening inflammation of the colon, lungs, or heart. For years, clinicians have debated whether these toxicities strike all patients equally. A new study from researchers at NYU Langone Health’s Perlmutter Cancer Center, published in the Journal of Translational Medicine, suggests they do not. The team found that melanoma patients of underrepresented minority ancestry experienced significantly more immune-related side effects than patients of non-Hispanic white ancestry, even when both groups received the same drugs, were treated at the same stage of disease, and had comparable access to care.

The research, led by Milad Ibrahim and Iman Osman along with a multidisciplinary team spanning dermatology, medical oncology, biostatistics, and population health, set out to address a persistent blind spot in cancer immunotherapy. Most studies of racial differences in melanoma outcomes have concentrated on social determinants of health, such as insurance status, geographic access to specialists, and delays in diagnosis. Those factors undeniably matter, but they leave open a fundamental question: do ancestry-associated biological differences themselves influence how patients respond to and tolerate immunotherapy? To isolate that question, the investigators designed their study around a single institution, NYU Langone Health, where patients of different ancestries were treated within the same health system and therefore had comparable access to care. That design choice is critical, because it helps separate biological variation from the socioeconomic confounders that have dominated the disparities literature.

The study enrolled 841 melanoma patients who received immune checkpoint inhibitors at Perlmutter Cancer Center, of whom 774 were non-Hispanic white and 67 were classified as underrepresented minority. Rather than relying solely on how patients described their own background, the researchers determined ancestry genetically, using whole-genome sequencing and principal component analysis to assign each patient to ancestry groups. The rigor of this approach paid off: the genetically derived ancestry assignments agreed with self-reported ancestry in 98.7 percent of cases, with an agreement coefficient of 0.99 and a 95 percent confidence interval of 0.97 to 1.00. This near-perfect concordance strengthens confidence that the ancestry categories used in the analysis reflect genuine patterns of genetic ancestry rather than misclassification, and it demonstrates that in this cohort, self-identification was a reliable proxy for genomic ancestry.

Before examining side effects, the team characterized the clinical differences between the two groups, and one demographic pattern stood out immediately. Among non-Hispanic white patients, melanoma was more prevalent in males, consistent with the well-documented male predominance of the disease in populations of European ancestry. Among underrepresented minority patients, however, melanoma was significantly more common in females, a difference that reached statistical significance with a p-value of 0.03. This reversal of the expected sex distribution hints that melanoma biology or risk factors may differ meaningfully across ancestry groups, and it adds to a growing body of evidence that melanoma in patients of African or other non-European ancestry arises in different anatomic and demographic contexts than the sun-exposure-driven disease typical of lighter-skinned populations.

The central finding of the study emerged when the researchers compared immune-related adverse events between the groups. Despite comparable melanoma stage at treatment, similar types of checkpoint inhibitor regimens, and equivalent treatment outcomes, underrepresented minority patients experienced significantly more immune-related adverse events than non-Hispanic white patients, and the difference held across all grades of toxicity. In other words, the excess toxicity was not confined to mild, easily managed side effects; it spanned the full spectrum of severity. Because the two groups were treated at the same institution and received comparable therapy, the authors argue that ancestry-associated biological factors, rather than differences in care, are the most plausible explanation for the disparity in toxicities.

To probe the biological mechanisms behind this pattern, the investigators turned their attention to autoantibodies, the immune system’s self-targeting antibodies that are thought to play a central role in immune-related adverse events. Using the KREX platform, a technology that profiles the full repertoire of autoantibodies circulating in a patient’s serum, the team compared autoantibody profiles between underrepresented minority and non-Hispanic white patients. The analysis revealed both overlapping and distinct profiles between the groups, with underrepresented minority patients exhibiting a greater number of unique autoantibodies. Crucially, these autoantibodies correlated with the development of checkpoint inhibitor toxicities, suggesting that the pre-existing or treatment-induced humoral immune landscape differs by ancestry in ways that translate directly into clinical risk.

Pathway enrichment analysis of the autoantibody targets added a mechanistic layer to the findings. The targets were significantly enriched for proteins involved in lymphocyte activation, immune signaling, and inflammatory regulation, a signature consistent with heightened immune priming and distinct humoral immune recognition in underrepresented minority patients who went on to experience immune-related adverse events. In practical terms, this means that the baseline immune state of these patients, shaped in part by their ancestry, may leave them biologically primed for the kind of overactive immune responses that checkpoint inhibitors can provoke. Toll-like receptor pathways, which act as sentinels of innate immunity, are among the immune signaling components implicated in such signatures, and their involvement fits with the idea that ancestry-linked variation in immune regulation can amplify the inflammatory consequences of releasing T cells from inhibition.

The clinical implications of the study are substantial. Immune-related adverse events are among the most important limiting factors in checkpoint inhibitor therapy: they force dose interruptions, require immunosuppressive treatment with corticosteroids or other agents, and in severe cases can permanently end immunotherapy or endanger the patient’s life. If patients of particular ancestry backgrounds carry a higher baseline risk of these toxicities, then ancestry could become a meaningful variable in clinical decision-making and risk stratification, informing how intensively patients are monitored, how early toxicities are investigated, and how treatment regimens are selected. The authors explicitly frame their conclusion in these terms, stating that the data support consideration of ancestry in clinical decision-making and risk stratification to improve both the safety and the effectiveness of immune checkpoint inhibitors in diverse patient populations.

The study also carries broader significance for the field of cancer immunotherapy research. Underrepresented minority patients remain markedly underrepresented in clinical trials of checkpoint inhibitors, which means that the safety and efficacy data guiding treatment worldwide derive disproportionately from populations of European ancestry. This study demonstrates concretely why that gap matters: a biological signal, visible in autoantibody profiles and reflected in toxicity rates, would have been invisible in a trial cohort composed only of non-Hispanic white patients. The finding that melanoma in underrepresented minority patients skews female further underscores that even the epidemiology of the disease differs across populations in ways that standard trial designs may not capture. As precision oncology moves toward tailoring treatment to individual biology, ancestry-linked immune variation is emerging as one more dimension that cannot be ignored.

There are, of course, important caveats to keep in view. The underrepresented minority group in the cohort comprised 67 patients, a substantial number for a single-institution genomic study but still modest relative to the non-Hispanic white majority, and the authors note that the work was shared early as a peer-reviewed, accepted version subject to further editorial refinement. The study was conducted within one health system in New York, and replication in other populations and geographic settings will be needed to confirm the findings and refine their generalizability. Nevertheless, the combination of rigorous genomic ancestry assignment, careful clinical phenotyping, and mechanistic autoantibody profiling makes this one of the most detailed examinations to date of how ancestry influences the tolerability of cancer immunotherapy. For a therapy class that now reaches hundreds of thousands of patients worldwide, the message is clear: the immune system’s response to having its brakes released is not universal, and understanding ancestry-linked differences in immune priming may be essential to delivering immunotherapy that is both effective and safe for everyone.

Subject of Research: The influence of patient genetic ancestry on immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors

Article Title: Impact of patient ancestry on melanoma immunotherapy immune-related adverse events

Article References: Ibrahim, M., Fa’ak, F., Dutt, A., Qiu, S., Onwumere, O., Xiong, J., Ferguson, R., Ahtar, N., Pan, Y., Kim, S., Lyu, C., Zhong, J., Schober, M., Li, H., Kirchhoff, T., & Osman, I. (2026). Impact of patient ancestry on melanoma immunotherapy immune-related adverse events. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08970-w

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08970-w

Keywords: melanoma, immune checkpoint inhibitors, immune-related adverse events, ancestry, autoantibodies, health disparities, immunotherapy, whole-genome sequencing, underrepresented minorities, immune priming, precision oncology, Journal of Translational Medicine