Red Blood Cell-Derived miR-93-5p Correlates with PD-1/PD-L1 Upregulation and Poor Prognosis in Lung Cancer.

Background: Lung cancer remains the deadliest malignancy. Although PD-1/PD-L1 immune checkpoint inhibitors have improved survival, their benefit is limited by persistent immune resistance. Identifying systemic regulators of tumor immune microenvironment may enhance therapeutic efficacy. We previously showed that RBC-derived miR-93-5p promotes PTEN loss and PI3K-AKT activation. This study examined whether RBC-derived miR-93-5p is associated with immune checkpoint activity and features of T-cell exhaustion in lung cancer. Methods: RBCs, RBC-derived exosomes, and plasma were isolated from 80 lung cancer patients and 30 controls, and tumor and matched noncancerous lung tissues were collected. miR-93-5p expression was quantified by droplet digital PCR. PD-1, PD-L1, CD8+ T-cell infiltration, CD69, IFN-γ, and TNF-α were evaluated by immunohistochemistry. Associations with clinicopathologic features and survival were statistically analyzed. Results: miR-93-5p levels in RBCs, their exosomes, and tumor tissues were significantly elevated in lung cancer. Higher miR-93-5p was associated with increased PD-1 and PD-L1 expression and reduced CD69, IFN-γ, and TNF-α, consistent with T-cell exhaustion. Elevated miR-93-5p correlated with advanced disease and reduced survival. Conclusions: RBC-derived miR-93-5p is associated with immune checkpoint activation, T-cell exhaustion, and poor clinical outcomes, suggesting impaired antitumor immunity. Targeting this axis may improve the efficacy of immunotherapy in lung cancer.