Y chromosome loss drives sex disparities in multiple myeloma by reshaping the immune landscape

Abstract Sex-based differences in cancer incidence and prognosis remain incompletely understood. Loss of the Y chromosome (LOY)-the most common somatic alteration in aging men-has been linked to poor outcomes across several tumor types. However, the clinical and biological relevance of LOY across cancers, particularly its potential contribution to the male predominance in multiple myeloma (MM), has not been fully elucidated. Here, we identify LOY as a major driver of MM pathogenesis, disease progression, and therapeutic response, establishing its pivotal role in mediating sex disparities in MM. To assess the clinical and biological impact of LOY, we developed a transcriptomic signature (Chr.Y.Score) based on nine stably expressed Y-linked genes. This score was applied to 5,389 male patients across 26 non-reproductive tumor types in The Cancer Genome Atlas (TCGA), and further extended to hematologic malignancies, including MM, using data from TCGA and the MMRF-COMMPASS study. We evaluated associations between Chr.Y.Score and key oncogenic features, including stemness, immune subtypes, genomic instability, clinical phenotypes, and patient outcomes. In MM, LOY was further characterized using both bulk RNA sequencing (LOYBR) and single-cell RNA sequencing (LOYSCR) to determine its presence in malignant plasma cells and immune cells within the tumor microenvironment. Functional studies were conducted to investigate the tumor-suppressive role of the Y-linked gene RPS4Y1 in MM. Pan-cancer analyses revealed that low Chr.Y.Score (Ylow) was associated with enhanced stemness, increased genomic instability, and activation of immune-related pathways. Clinically, Ylow status correlated with inferior overall survival and was enriched in aggressive tumor subtypes. In MM, LOY was detected not only in tumor cells but also in tumor-infiltrating immune cells. MM patients with Ylow tumors exhibited increased tumor mutational burden, elevated expression of immunosuppressive checkpoint molecules, and significantly worse clinical outcomes. Single-cell transcriptomic analysis demonstrated dynamic, cell type-specific LOY, especially in CD14⁺ monocytes and plasma cells, particularly among relapsed/refractory MM cases. Importantly, LOY in plasma cells predicted poor response to CAR-T cell therapy. LOY cells exhibited widespread dysregulation of immune regulatory genes across T cells, NK cells, and myeloid lineages, suggesting a profound remodeling of the immune landscape. Finally, we identify Y-linked gene RPS4Y1 as a tumor suppressor in male MM. Clinically, reduced RPS4Y1 expression was associated with disease progression, treatment resistance, and shortened survival. Mechanistically, loss of RPS4Y1 promoted M2 macrophage polarization and recruitment, thereby enhancing MM cell proliferation. Collectively, our findings identify LOY as a critical determinant of tumor progression and immune dysfunction in MM, in part through loss of RPS4Y1. This study uncovers a previously underappreciated mechanism driving sex disparities in MM and highlights LOY as a potential biomarker and therapeutic target for precision immunotherapy in male patients.