Intercellular communication plays an essential role in lung cancer (LC). One of the major players in cell‐cell‐communication is small extracellular vesicles (sEV). SEV trigger various biological responses by transporting cellular cargo to target cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. We report that prostaglandin E₂(PGE₂), a key inflammatory lipid mediator, specifically induces the sorting of miR‐574‐5p in sEV of A549 and 2106T cells. We found that sEV‐derived miR‐574‐5p activates Toll‐like receptors (TLR) 7/8, thereby decreasing PGE₂‐levels. In contrast, intracellular miR‐574‐5p induces PGE₂‐biosynthesis. Consequently, the combination of intracellular and sEV‐derived miR‐574‐5p controls PGE₂‐levels via a feedback loop. This was only observed in adeno‐ but not in squamous cell carcinoma, indicating a cell‐specific response to sEV‐derived miRs, which might be due to unique tetraspanin compositions. Hence, we describe a novel function of miR‐574‐5p unique to adenocarcinoma. Intracellular miR‐574‐5p induces PGE₂ and thus the secretion of sEV‐derived miR‐574‐5p, which in turn decreases PGE₂‐biosynthesis in recipient cells.
