Exonuclease 1 drives immune escape in lung adenocarcinoma by regulating the HIF-1α/PD-L1 axis

Abstract

Lung Adenocarcinoma (LUAD) represents the most prevalent subtype of lung cancer and additionally possesses the highest potential for lethality. EXO1 is overexpressed in multiple cancers and linked to poor prognosis, but its role in LUAD immune regulation remains unclear. Immunosuppression can be stimulated by HIF-1α, with the underlying mechanism being the upregulation of PD-L1. Our hypothesis is that EXO1 facilitates immune evasion in LUAD by influencing the HIF-1α-PD-L1 axis. Bioinformatic analysis of TCGA data and clinical samples validated EXO1 expression and prognosis correlation. In vitro and in vivo models including EXO1 knockdown/overexpression in LUAD cell lines were established. Functional assays (CCK-8, Transwell, wound healing, colony formation) and xenograft models assessed proliferation, migration, invasion and tumor growth. Immune interactions were evaluated via co-culture systems with T cells, flow cytometry, western blot and immunofluorescence. HIF-1α inhibitor PX-478 was used in rescue experiments. EXO1 was significantly overexpressed in LUAD tissues and cell lines, correlating with advanced tumor stage, poor survival, and reduced CD4+ /CD8+ T-cell infiltration. EXO1 knockdown suppressed LUAD cell proliferation, migration, invasion and tumor growth in mice, while overexpression promoted these malignant phenotypes. EXO1 upregulated PD-L1 expression, inhibited T-cell cytotoxicity (reduced granzyme B and perforin), and enhanced resistance to T-cell-induced apoptosis. EXO1 facilitated HIF-1α nuclear translocation; HIF-1α inhibition reversed EXO1-driven PD-L1 upregulation and restored T-cell infiltration, while partially attenuating the anti-apoptotic effects mediated by EXO1 in vivo. EXO1 drives LUAD progression and immune escape by regulating the HIF-1α-PD-L1 axis. It serves as a potential prognostic biomarker and therapeutic target, with HIF-1α inhibition offering a promising strategy to counteract EXO1-mediated immunosuppression in LUAD.