Secretory Nogo-B regulates Th2 differentiation in the lung cancer microenvironment

•Nogo-B is highly secreted by lung cancer cells.•The concentration of Nogo-B in the serum of lung cancer patients was significantly elevated and showed a significant positive correlation with tumor size.•ER stress and phosphorylation at S107 promote the secretion of Nogo-B in lung cancer cells.•Secretory Nogo-B may reshape the tumor immune microenvironment and promote tumor progression by inhibiting the function of tumor-infiltrating immune cells, especially Th2 cells. Nogo-B, a ubiquitously expressed member of the reticulon family, plays an important role in maintaining endoplasmic reticulum (ER) structure, regulating protein folding, and calcium homeostasis. In this study, we demonstrate that Nogo-B expression and secretion are upregulated in lung cancer and correlate to overall survival. Nogo-B is secreted by various cells, particularly lung cancer cells. ER stress and phosphorylation at serine 107 can induce Nogo-B secretion. Secretory Nogo-B suppresses the differentiation of Th2 cells and the release of type 2 cytokines, thus influencing the anti-tumor effects of Th2-related immune cells, including IgE+B cell class switching and eosinophil activation.