Loss of Y chromosome is associated with benefit from PD-1/PD-L1-based therapy in male lung adenocarcinoma

Chemoimmunotherapy is the standard first-line treatment for advanced, driver-negative NSCLC, yet predictive biomarkers are scarce. Loss of the Y chromosome is frequent in male cancers and linked to immune dysregulation, but its role in the lung cancer immune microenvironment and treatment response remains unclear. This study aims to investigate the predictive value of LOY for treatment benefit from anti-PD-1/PD-L1-based therapy and to characterize its relationship with the TIME in male patients with advanced LUAD. We performed a retrospective biomarker analysis of clinical and transcriptomic profiles from patients with advanced lung adenocarcinoma (LUAD) enrolled in three randomized trials (ORIENT-11, OAK, and POPLAR). LOY was inferred from bulk RNA-sequencing using a Y chromosome gene signature (YchrS). Survival outcomes were compared between LOY and wild-type Y (WTY) groups, stratified by treatment regimen. Single-cell RNA sequencing data from the GSE131907 cohort was further analyzed to characterize the biological context associated with Y-chromosome status. We found that LOY was associated with numerically more favorable survival outcomes in patients receiving anti-PD-1 plus chemotherapy in our ORIENT-11 trial, whereas no clear association was observed in the chemotherapy-only arm. Multivariable treatment-by-YchrS interactions were observed for PFS (interaction HR, 0.25; 95% CI, 0.10–0.67; Pinteraction = 0.005) and OS (interaction HR, 0.31; 95% CI, 0.12–0.81; Pinteraction = 0.017). In the OAK and POPLAR external cohorts, treatment-arm-specific survival patterns were directionally similar, but formal treatment-by-YchrS interactions were not statistically significant. Single-cell analysis revealed that LOY tumor cells exhibited increased expression of genes involved in antigen presentation, immune activation, and immune checkpoint pathways, consistent with an immunologically inflamed TIME. LOY specimens showed higher proportions of T follicular helper and CD8 + effector-memory T cells and lower proportions of regulatory T cells, while pooled CellChat analysis suggested stronger tumor–immune communication. Integrative stratification combining YchrS with tumor immune infiltration identified a subgroup (LOY/high ImmuneScore) with the most favorable outcomes following anti-PD-1-based therapy. Our findings support LOY as a promising candidate biomarker associated with treatment benefit from anti-PD-1/PD-L1-based therapy in male patients with advanced LUAD and reveal a potential association between LOY and an immunogenic tumor microenvironment, warranting further prospective validation.