M1 macrophage-derived exosomal miR-378a-3p enhances cisplatin sensitivity in non-small cell lung cancer by targeting...

Cisplatin (DDP) is a primary chemotherapy for non-small cell lung cancer (NSCLC), but its limited sensitivity necessitates new strategies to enhance its effectiveness. M1 macrophages in the tumor microenvironment amplify the anti-tumor efficacy of platinum-based chemotherapeutics, and M1 macrophage-derived exosomes (M1-Exos) have been shown to suppress tumor progression through microRNA delivery. This study aimed to investigate the role of M1-Exos in boosting DDP's anti-NSCLC effect and explore the underlying mechanisms.

M1 macrophages were induced from Mφ macrophages using IFN-γ, and M1-Exos were isolated and characterized. RT-qPCR confirmed the predominance of miR-378a-3p in M1-Exos. NSCLC cell and mouse models were treated with M1-Exos, mmu-miR-378a-3 inhibitor, and DDP. M1-Exos uptake was examined by immunofluorescence, M1 and M2 macrophage marker levels by RT-qPCR, apoptotic rates and macrophage ratios by flow cytometry, and cell proliferation and DDP IC₅₀ by MTT and colony formation assays. A dual-luciferase reporter assay explored miR-378a-3p's interaction with YAP1, and HIPPO pathway protein levels were quantified by western blot.

Both in vitro and in vivo experiments demonstrated that M1-Exos enhanced the anti-NSCLC effect of DDP by reducing tumor cell proliferation, enhancing apoptosis, and diminishing tumor growth. Mechanistically, M1-Exos activated the HIPPO signaling pathway by regulating p-YAP/YAP1, YAP1, TAZ, LATS1, and TEAD1 and encouraged M2 to M1 macrophage reprogramming. Inhibition of miR-378a-3p markedly reduced these effects. No obvious changes in serum ALT, AST, BUN, or BCr levels were observed among treatment groups.

In conclusion, M1-Exos, rich in miR-378a-3p, targets YAP1 to activate the HIPPO signaling pathway and shift macrophage phenotypes from M2 to M1, thereby augmenting DDP's anti-tumor impact through reduced NSCLC cell proliferation and increased apoptosis.