Y do T cells fail

Loss of the Y chromosome in blood cells occurs more commonly as men age and is associated with an increased risk of cancer and other inflammatory diseases. Cancer cells that lose Y chromosome expression are also considered a marker of poor outcome. Data now published in Nature link loss of tumor cell Y chromosomes with loss in immune cells that infiltrate the tumor microenvironment (TME). Using a wide variety of human tumors and a bespoke transcriptomic method to track chromosomal loss, the researchers found an association between Y chromosomal loss and worse survival outcomes with more aggressive tumor phenotypes. In addition, the degree of loss in tumor cells was predictive of the level of loss in other cell types in the TME, including immune cells and particularly in T cells. Mouse modeling indicated that loss of epithelial Y chromosomes can drive loss in these neighboring tumor-infiltrating T cells but not in blood cells. How does this work? The data seem to rule out a role for T cell exhaustion, but this is presently an open question. Nevertheless, the findings are intriguing and indicate the clinical need to assess Y chromosome stability of benign cells in the TME, with potential implications for T cell immunotherapies.

Original reference: Nature https://doi.org/10.1038/s41586-025-09071-2 (2025)