Core Viewpoint - The article discusses the biological inequality in cancer prevalence and mortality between men and women, highlighting the role of Y chromosome loss (LOY) as a significant factor in cancer progression and immune response in men [1][5][31]. Group 1: Research Findings - A study published in Nature by Chen Xingyu reveals how LOY affects both tumor cells and T cells, leading to poorer outcomes for male cancer patients [3][4][6]. - LOY is common in older men, with over 20% of men aged 60 and over showing detectable LOY in peripheral blood cells, previously considered a sign of aging but now linked to cancer progression [13][19]. - The study integrates data from over 4,000 male cancer samples and more than 1 million single-cell transcriptomic data, exploring the origins and clinical significance of LOY [19]. Group 2: Mechanisms of LOY - LOY not only occurs in tumor cells but also spreads to immune cells, particularly T cells, leading to a loss of anti-cancer capabilities [6][22]. - The presence of LOY in T cells correlates with immune suppression and functional exhaustion, indicating a systemic collapse in the immune response against cancer [21][28]. - The study suggests that LOY contributes to a "tumor-immune escape" mechanism, allowing cancer cells to proliferate unchecked [28]. Group 3: Clinical Implications - The findings propose a new LOY scoring system for survival prediction, which could aid in personalized treatment strategies for cancer patients [25][32]. - In cell therapies like CAR-T or TIL, the LOY status of reinfused cells should be a critical quality control metric to avoid reintroducing dysfunctional T cells [34]. - Future therapies targeting LOY-related immune deficiencies may represent a new direction in cancer immunotherapy [35]. Group 4: Gender Differences in Cancer - The study highlights that while the Y chromosome is male-specific, many key immune genes on the Y chromosome have homologous copies on the X chromosome in females, potentially explaining the stronger immune defenses in women [30][31]. - Understanding LOY provides insights into the molecular roots of gender differences in cancer susceptibility and outcomes [31][38].