Radiation‐induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5‐glutamine metabolism

Background Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence‐associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor‐derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation‐induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear. Methods Beta‐galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence‐associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation‐induced sEVs. Liquid chromatography–tandem mass spectrometry (LC–MS) was used to explore changes in the levels of proteins in radiation‐induced sEVs. Cell Counting Kit‐8 and colony formation assays were performed to investigate the function of radiation‐induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation‐induced sEVs and V‐9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence. Results We determined that the radiation‐induced SASP triggered OSCC cell proliferation. Additionally, radiation‐induced sEVs exacerbated OSCC cell malignancy. LC–MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation‐induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation‐induced sEVs in OSCC. Conclusion Radiation‐induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients.