SOX2 negatively regulates immune infiltration through inhibition of JAK-STAT signaling in the lung squamous carcinoma

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have improved outcomes for some patients, but many fail to respond, underscoring the need for predictive biomarkers. TCGA and single-cell RNA-seq data (GSE148071) demonstrated that SOX2 overexpression is associated with reduced immune infiltration, particularly diminished effector CD8? T cell presence. Functional assays in the LUSC cell line HCC95 showed that SOX2 knock-out activated JAK-STAT signaling and enhances the expression of immune related genes, thereby promoting a more immune-permissive tumor microenvironment. Conversely, the STAT1 inhibitor treatment reverses these features in SOX2-KO cells. Moreover, CUT&Tag sequencing revealed that SOX2 and STAT1 compete for binding at the promoters and enhancers of immune related genes (IRGs), modulating their expression. Taken together, our findings revealed that SOX2, a well-known oncogene, promotes immune evasion in LUSC through a tumor-extrinsic mechanism.