Exosomal miR-3662 originating from M2-polarized macrophages facilitates cisplatin resistance of lung adenocarcinoma cells through inhibiting the IRF8/RASSF5 cascade and boosting autophagy.

Cisplatin (DDP) resistance remains a major obstacle in lung adenocarcinoma (LUAD). This study investigates whether M2 macrophage‑derived exosomal miR‑3662 contributes to DDP resistance and uncovers the underlying mechanism. miR‑3662 was upregulated in LUAD tissues, further elevated in DDP‑resistant specimens and cell lines, and correlated with poor prognosis. Functionally, miR‑3662 overexpression enhanced DDP tolerance, clonogenicity, proliferation, and autophagy‑related activity while suppressing apoptosis; miR‑3662 inhibition reversed these effects. M2 macrophage exosomes transferred miR‑3662 into LUAD cells and promoted resistance, whereas GW4869 treatment or depletion of exosomal miR‑3662 attenuated this protection. Mechanistically, miR‑3662 directly bound the IRF8 3'UTR and reduced IRF8 protein expression. IRF8 occupied the RASSF5 promoter and activated its transcription. Consequently, miR‑3662‑mediated downregulation of the IRF8/RASSF5 axis induced cytoprotective autophagy. Restoration of IRF8 or RASSF5 counteracted M2‑exosome‑induced autophagy and resensitized cells to DDP. In xenograft models, targeting exosomal miR‑3662 restored IRF8/RASSF5 signaling, reduced autophagy markers, suppressed tumour growth, and improved DDP efficacy. These findings identify a novel microenvironment‑derived vesicular pathway where M2 macrophage exosomal miR‑3662 drives DDP resistance via IRF8/RASSF5 inhibition and autophagy activation, providing new insights into potential therapeutic strategies for overcoming platinum resistance in LUAD.