MiR-26b-5p in small extracellular vesicles derived from dying tumor cells after irradiation enhances the metastasis promoting microenvironment in esophageal squamous cell carcinoma.

Radiation therapy is effective in achieving local control in esophageal squamous cell carcinoma; however, changes in the tumor microenvironment induced by radiation can also promote metastasis. Dying tumor cells play vital roles in promoting the survival of living tumor cells; however, few studies have investigated the effects of dying tumor cells on the tumor microenvironment. Since myeloid-derived suppressor cells (MDSCs) and macrophages constitute the pre-metastatic niche (PMN), we used a 4-nitroquinoline-1-oxide induced in situ tumor model to investigate the effects of irradiation on MDSCs and macrophages in esophageal squamous cell carcinoma (ESCC). When primary tumor sites were irradiated, we observed an increase in MDSCs in the spleen and the deposition of PMN components in lung and liver. Enhanced MDSC accumulation and function were induced by small extracellular vesicles (sEVs) isolated from irradiated tumor-bearing mice. The MDSC induction function of sEVs after irradiation was reaffirmed using sEVs derived from ESCC cell lines. The irradiation-induced upregulation of miR-26b-5p in sEVs enhanced MDSC expansion and activation by targeting phosphatase and tensin homolog. Our results first elucidated a mechanism by which dying tumor cells enhanced the deposition of PMN components and potentiated MDSCs in ESCC after irradiation. sEVs played a vital role in mediating signals between the primary tumor and the microenvironment to form a metastasis-promoting microenvironment after irradiation. Furthermore, miR-26b-5p or PI3K/AKT signaling pathway inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes.