Aurora A‐Mediated Exosomal Secretion of <scp>miR</scp> ‐644a Promotes T‐Lymphocyte Apoptosis Through the <scp>NOXA</scp> / <scp>p4E</scp> ‐ <scp>BP1</scp> / <scp>MCL</scp> ‐1 Pathway

Lung cancer continues to be the primary contributor to cancer-related mortality worldwide. While immunotherapy markedly improves outcomes for many patients, clinical evidence indicates that non-small-cell lung cancer (NSCLC) patients with elevated Aurora A expression exhibit reduced therapeutic responses to immune checkpoint blockade. Elucidating the underlying mechanisms may unlock novel strategies to enhance the clinical benefits for this subset. In this study, we characterised cellular senescence and tumour microenvironment interactions using lung cancer cell lines with different Aurora A expression levels. H23 (high Aurora A expression) and A549 (low Aurora A expression) cells were selected to model tumour-immune crosstalk. Tumour-infiltrating lymphocytes (TILs) were isolated and activated via anti-CD28 costimulation. Through gain- and loss-of-function experiments, we established the optimal conditions to induce T-lymphocyte apoptosis and identified critical cell ratios and culture durations. In these co-culture systems, immune checkpoint inhibitors more effectively suppressed Aurora A-low tumour growth. Mechanistically, Aurora A overexpression exacerbated T-lymphocyte apoptosis via the NOXA-MCL-1 pathway. Further analysis revealed that Aurora A disrupts the eIF4G:eIF4E complex by suppressing p4E-BP1, thereby up-regulating the pro-apoptotic factor NOXA while down-regulating the anti-apoptotic factor MCL-1. Aurora A-driven T-lymphocyte apoptosis via the NOXA-MCL-1 axis compromises PD-1/PD-L1-mediated immune responses, providing a molecular rationale for immunotherapy resistance in Aurora A-high NSCLC patients. Targeting this pathway may restore T-cell viability and improve therapeutic outcomes.