BACE2 is a prognostic biomarker and induced macrophage M2 polarization in Non-Small Cell Lung Cancer

BACE2 has gained attention for its upregulation in various human cancers, suggesting relevance in cancer biology. However, its specific role in tumor growth and the tumor immune microenvironment (TIME) remains underexplored. We conducted bioinformatics analyses using pan-cancer datasets to assess BACE2 expression patterns and its correlation with patient outcomes. Additionally, we investigated associations with immune-related genes and immune cell infiltrations in tumor microenvironments. A BACE2 knockdown lung cancer model was established to evaluate its impact on Sorafenib efficacy and PD-L1 inhibitor-induced antitumor immune responses. BACE2 was significantly upregulated in multiple cancers compared to normal tissues and associated with poorer patient outcomes. It played a critical role in modulating immune-related gene expression and promoting immune cell infiltrations within tumors. In vitro and in vivo experiments showed that BACE2 knockdown inhibited M2 macrophage polarization, suppressed lung tumor progression, and enhanced Sorafenib efficacy by increasing activated immune cell infiltrations. Similarly, BACE2 knockdown potentiated PD-L1 inhibitor-induced antitumor immune responses in lung cancer models. This study underscores BACE2's pivotal role in lung cancer tumorigenesis and its influence on the tumor immune microenvironment. Inhibiting BACE2 could enhance current treatment effectiveness in lung cancer therapy, offering promising avenues for improving patient outcomes.