Y chromosome loss in cancer

Abstract

Loss of the Y chromosome (LOY) in male patients with cancer is associated with poor prognosis but the reason for this is unclear. Using a combination of mouse models and single-cell RNA sequencing analysis of human tumors, Chen et al. make the intriguing observation that epithelial tumors with LOY often occur in microenvironments where infiltrating, non-transformed immune cells — particularly CD4⁺ and CD8⁺ T cells — had also lost their copy of the Y chromosome. Tumor-infiltrating T cells with LOY showed features normally associated with a muted anti-tumor activity. Together, these data suggest that concomitant LOY in malignant cells and proximal immune cells creates an immunosuppressive milieu that favors aggressive tumor growth and poor outcomes for patients. Perhaps one of the most fascinating questions emanating from the study is how coordinated LOY occurs. Another is how LOY alters immune cell activity given that the function of the small gene-poor Y chromosome has traditionally been thought to be restricted to male development. These questions will need to be answered, but for now, the study provides a fascinating example of the way crosstalk between malignant and immune cells can affect disease outcomes.

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