In a groundbreaking study published in Nature, researchers at Cedars-Sinai have unveiled a critical link between the loss of the Y chromosome in male cancer patients and the aggressiveness of their tumors. This new research reveals that when both the cancer cells and the immune cells within the tumor microenvironment lose the Y chromosome, clinical outcomes worsen significantly. The findings open a new frontier in understanding how sex chromosome alterations influence cancer biology and the efficacy of immunotherapies, with broad implications for treatment strategies in male patients.
The Y chromosome, a defining genetic element for biological males, is known to gradually disappear from certain somatic cells as men age. While its loss in blood cells has been documented and correlated with health risks, the consequences of Y chromosome loss in cancer cells and immune cells within tumors have remained poorly understood. The Cedars-Sinai investigators have now illuminated the complex interplay between Y chromosome presence, tumor progression, and immune competence, demonstrating that its concurrent loss in both tumor and immune cells creates a tumor microenvironment conducive to cancer proliferation and immune evasion.
Previous research from Cedars-Sinai had established that bladder cancer cells lacking the Y chromosome could effectively escape immune surveillance, facilitating unchecked tumor growth. Intriguingly, these Y chromosome-deficient tumors also displayed a paradoxical increased sensitivity to immune checkpoint blockade therapy, which reinvigorates the immune system’s attack against cancer. Building on these insights, the current study, led by Dr. Simon Knott and Dr. Dan Theodorescu, expanded the investigation to encompass multiple cancer types using extensive publicly available genomic and transcriptomic datasets.
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Unexpectedly, the researchers discovered that the loss of the Y chromosome was not confined to cancerous epithelial cells but was also prominently present in immune cells infiltrating the tumor. This finding was particularly striking; tumors displaying Y chromosome loss in both compartments—cancer cells and immune cells—were strongly associated with highly aggressive tumor phenotypes and poor patient survival. This dual loss appears to compromise the immune system’s ability to mount an effective anti-tumor response, allowing malignant cells to thrive and spread more rapidly.
Delving deeper into the mechanisms, the scientists hypothesized that Y chromosome loss in tumor-infiltrating immune cells, such as T lymphocytes, impairs their functional capabilities. T cells are critical components of the adaptive immune system, responsible for recognizing and killing cancer cells. Loss of sex chromosome genes in T cells may disrupt normal immune signaling pathways, leading to diminished cytotoxic activity and failure to contain the tumor’s growth. This immune malfunction dovetails with the increased malignancy of cancer cells likewise missing the Y chromosome, resulting in a potent combination that undermines effective tumor control.
To validate their computational analyses, the investigators employed orthogonal methods, including fluorescence in situ hybridization and single-cell sequencing of patient tumor samples, confirming the concurrent absence of the Y chromosome in both tumor and immune cells. Moreover, preclinical models further substantiated these observations, demonstrating that tumors with this chromosomal alteration exhibited accelerated progression and resistance to conventional therapies, underscoring the clinical relevance of the findings.
One of the most transformative implications of this work lies in its potential impact on cancer immunotherapy, particularly T-cell-based treatments such as adoptive cell transfer therapies. These therapies involve harvesting T cells from patients, genetically or chemically modifying them to enhance anti-tumor efficacy, and reinfusing them to combat the cancer. The study posits that T-cell products derived from cells lacking the Y chromosome may be intrinsically less effective, raising a crucial question about current manufacturing practices and patient selection in these therapies.
Dr. Knott emphasized the need for incorporating screening protocols to detect Y chromosome status in T-cell therapies prior to infusion. This precaution could ensure that only robust, Y chromosome-intact T cells are utilized, thereby improving therapeutic success rates. Additionally, recognizing the prevalence of Y chromosome loss among older men—who represent a substantial proportion of cancer patients—this work calls for personalized approaches that account for chromosomal mosaicism in immune and tumor cells.
The study also stimulates fascinating questions about the biological underpinnings of Y chromosome loss. Unlike mutations or deletions in oncogenes and tumor suppressor genes, the disappearance of an entire chromosome is a relatively overlooked but impactful alteration. Understanding why the Y chromosome is lost in these distinct cell populations within tumors, and how this loss mechanistically alters cellular function at the molecular level, will be essential for developing targeted interventions and improving precision oncology paradigms.
Beyond direct therapeutic considerations, these discoveries shine a spotlight on the intersection of aging, sex chromosome biology, and cancer. With aging known to increase the prevalence of mosaic loss of the Y chromosome in hematopoietic and other tissues, this phenomenon might underlie the heightened cancer risk and poorer prognoses observed in elderly male patients. It also raises the prospect that restoration or compensation for Y chromosome gene function could emerge as a novel therapeutic avenue.
Dr. Robert Figlin, interim director of Cedars-Sinai Cancer, highlighted the significance of these findings within the broader landscape of precision medicine. Tailoring cancer treatment not only to molecular mutations but also to chromosomal and sex-specific factors represents an important stride in addressing the heterogeneity of cancer and improving outcomes. Ongoing research efforts are now focused on elucidating how best to integrate Y chromosome status into clinical diagnostics and how to design therapies that effectively counteract the detrimental effects of its loss.
In conclusion, the Cedars-Sinai team’s research represents a milestone in cancer biology, revealing that the concurrent loss of the Y chromosome in both malignant and immune cells fosters a tumor microenvironment that facilitates aggressive disease and undermines immune defense. This dual chromosomal loss compromises T-cell function and correlates with poor patient outcomes across multiple cancer types. By alerting the medical and research communities to the importance of Y chromosome integrity, especially in the context of immunotherapies, these findings pave the way for refined diagnostic tools and personalized treatment approaches that could significantly benefit male cancer patients worldwide.
Subject of Research:
Loss of the Y chromosome in cancer and immune cells and its impact on cancer progression and immunotherapy effectiveness
Article Title:
Concurrent loss of the Y chromosome in cancer and T cells impacts outcome
News Publication Date:
4-Jun-2025
Web References:
http://dx.doi.org/10.1038/s41586-025-09071-2
References:
Cedars-Sinai researchers, Nature, DOI: 10.1038/s41586-025-09071-2
Keywords:
Cancer cells, Cancer research, Y chromosome loss, Tumor microenvironment, Immune cells, T cells, Immunotherapy, Precision medicine, Aging, Male cancer patients
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