Red Blood Cell‐Derived Exosomal miR‐93‐5p Promotes Lung Cancer Progression through PTEN Suppression

Abstract Red blood cells (RBCs), which are enucleated and mitochondria‐deficient, have traditionally been considered essential for gas exchange and systemic metabolic regulation. Here, an unrecognized role for RBCs in promoting lung cancer progression is identified. In a cohort of 226 lung cancer patients and 239 healthy controls, significantly elevated levels of miR‐93‐5p are observed in RBCs and RBC‐derived exosomes, but not in plasma, with higher levels correlating with advanced stage and poor prognosis. Functional assays demonstrate that RBC‐derived exosomal miR‐93‐5p is transferred to tumor cells, where it suppresses PTEN and enhances proliferation, migration, and invasion. Conversely, exosomes released by lung cancer cells deliver miR‐93‐5p to RBCs, thereby augmenting its abundance within RBCs. Inhibition of miR‐93‐5p or restoration of PTEN abrogates these effects. In both subcutaneous and orthotopic mouse models, RBC‐derived exosomal miR‐93‐5p accelerates tumor growth and reduces survival, whereas therapeutic delivery of antisense oligonucleotides targeting miR‐93‐5p suppresses tumor burden, reduces metastasis, and prolongs survival. Together, the novel function of RBCs as active participants in tumorigenesis is reported through exosomal transfer of oncogenic miR‐93‐5p, establishing a bidirectional tumor‐RBC‐tumor communication axis that promotes malignancy and offers new diagnostic and therapeutic opportunities in lung cancer.