Low circulating miR-5193 promotes PD-L1-mediated immune evasion and relates to immune checkpoint inhibitor response in esophageal cancer.

Low levels of circulating tumor-suppressor microRNAs are associated with cancer progression and poor prognosis. However, their role in immune evasion and response to immune checkpoint inhibitors (ICIs) remains unclear. We aimed to identify a PD-L1-targeting tumor-suppressor microRNA downregulated in esophageal squamous cell carcinoma (ESCC). Four tumor-suppressor microRNAs (miR-5193, miR-3117-3p, miR-802, and miR-651-3p) predicted to target programmed cell death ligand 1 (PD-L1) were selected. Plasma levels of miR-5193 were significantly lower in ESCC patients than in healthy volunteers. In 122 consecutive ESCC patients, low plasma miR-5193 was associated with advanced tumor depth and pathological stage and was an independent prognostic factor. In ESCC cells, miR-5193 suppressed PD-L1 expression. In a co-culture model of tumor cells and T cells, miR-5193 overexpression enhanced T cell antitumor activity by suppressing PD-L1. Among 56 ESCC patients treated with or without ICIs for recurrence, miR-5193 levels showed a trend toward an inverse association with PD-L1 tumor proportion score. In the low miR-5193 group, disease control rate was higher and ICI-treated patients showed a trend toward longer progression-free survival. Low levels of miR-5193 contribute to ESCC progression and poor outcomes and may serve as a biomarker reflecting tumor immune status and ICI-related outcomes.