BCL2A1high CD8+ T Cells Are a Survival-Associated Predictor of Immune Checkpoint Blockade Response in Lung Adenocarcinoma

<b>Background</b>: Immune checkpoint blockade (ICB) has revolutionized lung adenocarcinoma (LUAD) therapy, yet predictive bio-markers remain suboptimal. We hypothesized that <i>BCL2A1</i> expression in CD8⁺ T cells may reflect immune endurance and complement PD-L1 in predicting ICB response. <b>Methods</b>: Integrating bulk and single-cell RNA-seq across multiple LUAD cohorts, this study performed differential expression, survival, and pathway analyses in a discovery cohort (<i>n</i> = 60) and validated findings across five independent cohorts (<i>n</i> = 126). <b>Results</b>: Single-cell profiling identified <i>BCL2A1</i> enrichment in tissue-resident memory and proliferating subsets that appeared preferentially expanded in responders; cell-cell communication analysis revealed that <i>BCL2A1</i>^high CD8⁺ T cells exhibited significantly enhanced outgoing signaling capacity (<i>p</i> = 0.0278), with proliferating subsets serving as intra-CD8⁺ coordination hubs and MIF pathway interactions achieving the highest intensity among all axes examined. <i>BCL2A1</i> was significantly upregulated in responders (FDR < 0.05) and associated with improved ICB survival (HR = 0.43, <i>p</i> < 0.05), but not in non-ICB settings, suggesting treatment-specific prognostic relevance. A tri-marker model integrating <i>BCL2A1</i>, <i>PD-L1</i> (CD274), and a 27-gene HOT score demonstrated favorable predictive performance (AUC = 0.826 discovery; macro-AUC = 0.774 validation), outperforming <i>PD-L1</i> alone (AUC = 0.706) and established signatures including TIDE, IPS, TIS, and IFNG. Cross-platform simulations suggested high reproducibility (ρ = 0.982-0.993). <b>Conclusions</b>: These findings suggest <i>BCL2A1</i> may serve as a bio-marker of CD8⁺ T-cell survival and enhanced intercellular coordination, and its integration with PD-L1 and immune activation markers may yield a reproducible ICB response predictor, pending clinical validation.