upregulation is correlated with an immunosuppressive tumor microenvironment and predicts unfavorable outcome of immune checkpoint therapy in non-small cell lung cancer.

Background: Previous studies found that was recurrently mutated and aberrantly expressed in multiple cancers, and the loss function of promoted the formation of cancer-initiating cells in several cancers. However, in some types of cancer, upregulation could lead to epithelial-mesenchymal transition (EMT). The role of in cancer progression, which appears to be cancer-type-specific, is largely unknown.

Methods: QRT-PCR and immunochemistry were used to verify the expression of in non-small cell lung cancer (NSCLC). QRT-PCR and Western blot were used to detect the influence of siFAT1 knockdown on the expression of potential targets of in NSCLC cell lines. GEPIA, KM-plotter, CAMOIP, and ROC-Plotter were used to evaluate the association between and clinical outcomes based on expression and clinical data from TCGA and immune checkpoint inhibitors (ICI) treated cohorts.

Results: We found that upregulation was associated with the activation of TGF-β and EMT signaling pathways in NSCLC. Patients with a high expression level tend to have a poor prognosis and hard to benefit from ICI therapy. Genes involved in TGF-β/EMT signaling pathways ( and ) were downregulated upon knockdown of . Genomic and immunologic analysis showed that high cancer-associated fibroblast (CAF) abundance, decreased CD8 T cells infiltration, and low TMB/TNB were correlated with the upregulation of , thus promoting an immunosuppressive tumor microenvironment (TME) which influence the effect of ICI-therapy.

Conclusion: Our findings revealed the pattern of upregulation in the TME of patients with NSCLC, and demonstrated its utility as a biomarker for unfavorable clinical outcomes, thereby providing a potential therapeutic target for NSCLC treatment.