The potential of circITFG2 as a therapeutic target in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options and poor patient prognosis. Emerging evidence suggests that circular RNAs (circRNAs) play critical regulatory roles in cancer progression, but their involvement in LUSC remains largely unexplored. This study aimed to investigate the functional role of circular RNA ITFG2 (circITFG2) in LUSC pathogenesis and to evaluate its potential as a novel therapeutic target. METHODS: The expression profile of circRNAs in clinical LUSC samples was analyzed via the Arraystar human circRNA microarray, and the level of circITFG2 was validated via Arraystar circular RNA microarray chip sequencing. Functional characterization was performed through in vitro cellular assays, including proliferation, migration, and invasion experiments, while tumor growth in vivo was assessed with a xenograft mouse model. Molecular mechanisms and immunomodulatory effects were elucidated and evaluated through Western blotting, quantitative reverse-transcription polymerase chain reaction (RT-qPCR), RNA immunoprecipitation (RIP), luciferase reporter assays, and T cell-mediated natural cytotoxicity experiments. RESULTS: Both bioinformatics and experimental analyses revealed that circITFG2 was significantly downregulated in LUSC tissues. Functional studies demonstrated that circITFG2 overexpression markedly suppressed LUSC cell proliferation, migration, and invasion. Xenograft experiments also showed that tumors in the circITFG2-overexpression group were significantly smaller than those in the control group. Further investigations identified integral membrane protein 2A (ITM2A) as a key downstream effector. Overexpression of circITFG2 competitively bound miR-526b-5p to upregulate ITM2A, ultimately activating the autophagy pathway to promote programmed death-ligand 1 (PD-L1) degradation and thereby enhancing antitumor immune responses. CONCLUSIONS: This study identifies circITFG2 as a frequently underexpressed regulatory circRNA in LUSC. Its overexpression inhibited cancer cell proliferation, migration, and invasion while reducing tumor growth in xenografts. Oe-circITFG2 competitively bound miR-526b-5p, upregulating ITM2A to activate autophagy-mediated PD-L1 degradation and enhance antitumor immunity.