NME4 modulates PD-L1 expression via the STAT3 signaling pathway in squamous cell carcinoma.

NME4, also named Nm23-H4, is a contraction of NME/NM23 Nucleoside Diphosphate Kinase 4, whose major role is the synthesis of nucleoside triphosphates. However, its association with programmed death ligand 1 (PD-L1) remains far from understood. Herein, it was discovered that silencing NME4 can lead to the marked downregulation of PD-L1, with phosphorylated STAT3 at the 705th serine being inactivated in vitro in esophageal squamous cell carcinoma (ESCC) cell lines. To further validate the association between NME4 and PD-L1 that was observed in cell lines, Pearson correlation analysis was performed on the data regarding the transcriptomic RNA sequencing of NME4 and PD-L1 in cervical squamous cell carcinoma (CSCC), which pathologically highly resembles ESCC in terms of tumor origin, obtained from the GEPIA database. It was demonstrated that their correlation was significant but negative between NME4 and PD-L1 in CSCC. To the best of our knowledge, this is the first report describing a modulation exerted by NME4 over PD-L1 in the background of squamous cell carcinoma, strongly suggestive of the underlying role of NME4 working to exclude CD8 T cells from infiltrating into the squamous cell carcinoma microenvironment.