In a scientific breakthrough that could change the face of male cancer treatment, a recent study has uncovered the mysterious link between the loss of the Y chromosome in male immune cells and weakened immunity against tumors.
This relationship explains why cancer death rates are higher among men with missing Y chromosomes in their immune cells.
The loss of the Y chromosome—which males normally carry in every cell alongside the X chromosome—is a common, non-hereditary genetic change associated with aging. Although it has been linked for years to increased mortality from malignant tumors, the biological mechanism behind this phenomenon has remained mysterious.
Researchers from the University of Arizona Comprehensive Cancer Center tracked the impact of Y chromosome loss on T cells in the fight against cancer. They discovered for the first time that the loss of the Y chromosome in white blood cells, particularly helper and cytotoxic T cells, weakens the immune system's ability to fight tumors.
The team also found that patients with double Y chromosome loss—either in cancer cells or surrounding immune cells—have more aggressive tumors and lower survival rates.
Researchers explain that immune cells with the loss of the Y chromosome transform into a zombie-like version, losing their ability to recognize and destroy cancer cells efficiently, which explains why tumors become more aggressive in these patients.
The negative impact is compounded when Y chromosome loss occurs in both cancer cells and surrounding immune cells, as these patients have the worst treatment outcomes. This observation opens the door to the development of new diagnostic tests that can predict tumor aggressiveness and response to treatment based on Y chromosome status.
"These findings represent a significant leap in our understanding of how tumors evade the immune system," said lead researcher Dr. Dan Theodorescu. "We hope they will pave the way for developing more effective therapeutic approaches, such as screening cells used in immunotherapy (such as CAR-T therapy) for Y chromosome integrity before use."
The journey of this discovery began when Theodorescu, while working at Cedars-Sinai Medical Center, noticed a potential link between the loss of the Y chromosome and cancer treatment outcomes, which prompted him to collaborate with Dr. Simon Nutt to investigate this hypothesis.
These findings not only add to scientific knowledge, but also lay the foundation for a new era in personalized cancer medicine, whereby treatment plans tailored to men based on their Y chromosome status could soon be designed, potentially saving millions of lives worldwide.
The results were published in the journal Nature.
