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

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.