TCF21 Downregulation Induces ERO1A Expression and Upregulates IDO1 to Trigger Immune Escape in Lung Adenocarcinoma

ABSTRACT Transcription factor TCF21 is downregulated in lung adenocarcinoma (LUAD), contributing to poor treatment outcomes. This study explores its role in regulating CD8 + T cell‐mediated antitumor immunity and metastasis. TCF21 expression was analyzed via TCGA. Downstream target ERO1A was identified using JASPAR prediction, validated by dual‐luciferase/ChIP assays. LUAD mouse models and cell experiments (Transwell, flow cytometry, LDH/ELISA) assessed impacts on metastasis and CD8 + T cell function. The results showed that TCF21 overexpression inhibited LUAD migration/invasion and enhanced CD8 + T cell cytotoxicity. Mechanistically, TCF21 repressed ERO1A transcription, reducing IDO1 expression. Conversely, ERO1A overexpression promoted metastasis and suppressed CD8 + T cell activity via IDO1 upregulation. Knockdown of ERO1A or IDO1 blockade reversed the pro‐tumor effects of TCF21 loss. In conclusion, TCF21 downregulation in LUAD activates the ERO1A‐IDO1 axis, enabling immune escape from CD8 + T cell killing and accelerating malignancy.