Exosomal transfer of macrophage-derived NEAT1 enhances DNA damage response and confers cisplatin resistance in lung adenocarcinoma via the MAD1L1/p53 axis.

Cisplatin (DDP) resistance remains a major therapeutic obstacle in non-small-cell lung cancer (NSCLC). Tumor-associated macrophages (TAMs) are known to promote chemoresistance via exosomal signals, but whether exosomal long non-coding RNA NEAT1 contributes to this process is unclear. In this study, we found that exosomes derived from DDP-treated macrophages were enriched with NEAT1 and delivered it to A549 cells. This transfer enhanced the DNA damage response, promoted cell-cycle progression, and reduced DDP-induced apoptosis. Through RNA-sequencing and luciferase reporter assays, we identified MAD1L1 as a key downstream target of NEAT1. NEAT1 was enriched at the MAD1L1 promoter, upregulated its expression, and subsequently suppressed the p53/p21/Bax axis, thereby fostering a chemoresistant phenotype. In vivo, exosomal NEAT1 promoted tumor growth in DDP-treated xenografts, while NEAT1 knockdown reversed this effect and restored p53 pathway activity. Collectively, our work unveils a novel TAM-exosome-NEAT1-MAD1L1/p53 signaling axis that drives cisplatin resistance in lung adenocarcinoma, highlighting NEAT1 and its intercellular delivery as potential therapeutic targets to overcome chemoresistance.