FARSB downregulation by SPI1 modulates lung adenocarcinoma progression and immune microenvironment via mTOR pathway.

Background: Phenylalanyl-TRNA Synthetase Subunit Beta (FARSB) is implicated in the progression of multiple cancers and represents a potential therapeutic target. However, its role in lung adenocarcinoma (LUAD) progression and the immune microenvironment remains poorly understood, warranting further investigation into its regulatory mechanisms.

Methods: We conducted bioinformatics analyses to investigate the expression levels of FARSB in LUAD, identify enriched pathways, and assess its correlation with patient prognosis and CD8+ T cell infiltration. Bioinformatics analysis was also employed to explore the transcriptional repression of FARSB by SPI1 and to validate the targeting relationship between SPI1 and FARSB. qRT-PCR was utilized to measure the mRNA expression of FARSB and SPI1, while Western blot was used to detect the expression of FARSB, SPI1, PD-L1, and related signaling pathway proteins. Functional assays were performed, including CCK-8 assay for cell viability, EdU incorporation for cell proliferation, and flow cytometry for apoptosis analysis. CFSE staining was used to analyze CD8+ T cell proliferation, and flow cytometry was used to assess the expression of cytokines IFN-γ, GZMB, and TNF-α.

Results: FARSB expression was significantly upregulated in LUAD tissues and cells, and it inhibited CD8+ T cell infiltration. Mechanistically, FARSB activated the mTOR signaling pathway, enhancing LUAD cell viability, proliferation, and anti-apoptotic capabilities, consequently promoting CD8+ T cell exhaustion. The transcription factor SPI1 repressed FARSB expression, thus inhibiting LUAD progression and promoting CD8+T cell anti-tumor immunity.

Conclusion: SPI1 downregulated FARSB expression through transcriptional repression, thereby blocking the mTOR signaling pathway and suppressing LUAD progression and promoting CD8+T cell anti-tumor immunity.