Extracellular vesicles derived from irradiated oral squamous cell carcinoma cells inhibits M2 macrophage polarization by the miR-198-5p/MYD88 axis

Extracellular vesicle (EV)-mediated delivery of microRNAs (miRNAs) plays a crucial role in intercellular communication between tumor cells and their microenvironment, thereby influencing the response to radiotherapy. This study aims to elucidate the effects of EVs derived from irradiated tumor cells on macrophage polarization in oral squamous cell carcinoma (OSCC) and to explore the underlying mechanisms involved. The expression levels of miR-198-5p within EVs isolated from both normoxic and irradiated OSCC cells were quantified. Subsequently, we assessed the impact of these EVs on macrophage polarization by analyzing the expression profiles of M1 and M2 markers. Additionally, bioinformatics analyses were performed to predict potential targets for miR-198-5p, with dual-luciferase assays confirming its interaction with myeloid differentiation primary response 88 (MYD88). miR-198-5p was found to be enriched in EVs derived from irradiated OSCC cells (IR-EVs), facilitating its transfer into macrophages. IR-EVs abundant in miR-198-5p inhibited an M2 macrophage polarization phenotype. Furthermore, it was demonstrated that miR-198-5p directly targets MYD88, leading to a reduction in its expression within macrophages. Importantly, overexpression of MYD88 mitigated the inhibitory effect exerted by miR-198-5p-rich IR-EVs on M2 polarization of macrophages. Our findings indicate that EVs rich in miR-198-5p derived from irradiated OSCC cells inhibit M2 polarization of macrophages through inhibition of MYD88 expression; thus suggesting that encapsulating miR-198-5p within EVs may represent a promising therapeutic strategy for OSCC.