Y Chromosome Loss Linked to Worse Cancer Outcomes in Men

Dual loss in tumors and immune cells linked to poor prognosis.

A study by Cedars-Sinai researchers has found that the loss of the Y chromosome in both cancer cells and immune cells within male tumors correlates with poor patient outcomes. Published in Nature, the research expands on earlier findings that indicated a role for Y chromosome loss in bladder cancer progression.

The Y chromosome, one of two sex chromosomes in mammals, is present only in biological males. It is not unusual for some cells in older men to lose this chromosome. Previous work from Cedars-Sinai in 2023 demonstrated that bladder cancer cells without a Y chromosome were better at evading immune detection, though these same tumors were more responsive to immune checkpoint therapy.

Expanding the scope beyond bladder cancer

To explore whether these findings extended to other cancers, the team used public datasets to assess Y chromosome loss across a variety of tumor types. They discovered that not only cancer cells, but also immune cells in the tumor environment frequently lost the Y chromosome in male patients.

The simultaneous loss of the Y chromosome in both cancer and immune cells was associated with aggressive tumor behavior and compromised immune function, suggesting a biological mechanism contributing to worse outcomes. This dual loss appeared to disrupt the normal immune response, potentially reducing the effectiveness of standard immune surveillance.

Implications for immunotherapy and T-cell treatments

The findings may be particularly relevant for patients undergoing cellular immunotherapies, such as T-cell therapy. These treatments involve modifying a patient’s T cells to better recognize and attack cancer. The study suggests that assessing Y chromosome status in T cells before they are used in treatment may be important, as Y chromosome–deficient T cells could be less effective.

Additional validation was conducted using tumor samples and preclinical models, strengthening the study’s conclusions.

Further research required to tailor therapies

Given the prevalence of Y chromosome loss in older men, the study underscores the need for further research to determine how this phenomenon influences treatment response. These insights could contribute to more personalized approaches in cancer therapy, especially for immunotherapies.

Reference: Chen X, Shen Y, Choi S, et al. Concurrent loss of the Y chromosome in cancer and T cells impacts outcome. Nat. 2025. doi: 10.1038/s41586-025-09071-2

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