UBA1 enhances phagocytosis by suppressing CD47 expression in small cell lung cancer.

INTRODUCTION: Small cell lung cancer (SCLC) exhibits a limited overall response rate to immunotherapy, largely due to its highly immunosuppressive microenvironment. CD47, an innate immune checkpoint frequently overexpressed on SCLC cells, contributes to immune evasion by inhibiting macrophage-mediated phagocytosis. Here, we uncover a previously unrecognized immunoregulatory function of ubiquitin-like modifier activating enzyme 1 (UBA1) in SCLC. METHODS: We analyzed UBA1 expression in 16 SCLC patients undergoing immunotherapy (immunohistochemistry). Functional studies used UBA1-knockdown and overexpression SCLC cell lines (H446, H82) to assess phagocytosis, macrophage polarization, and CD47 regulation. Mechanistic insights were obtained via Hippo pathway activation assays (enhancing MST1/YAP phosphorylation). In vivo subcutaneous xenografts in nude mice evaluated tumor growth and macrophage infiltration. RESULTS: High UBA1 expression correlated with improved immunotherapy response and prolonged progression-free survival. UBA1 activates the Hippo signaling pathway, enhancing MST1 and YAP phosphorylation and thereby repressing CD47 transcription. UBA1 overexpression attenuates surface CD47 levels in SCLC cells, potentiates macrophage phagocytic activity, and promotes a pro-inflammatory macrophage polarization, whereas UBA1 knockdown exerts opposing effects. In vivo xenograft models further confirm that UBA1 deficiency diminishes tumor susceptibility to phagocytosis and accelerates tumor progression. CONCLUSION: UBA1 enhances phagocytosis by suppressing CD47 through the Hippo-YAP pathway, improving immunotherapy efficacy in SCLC. Collectively, these findings reveal that the UBA1-CD47 axis represents a potentially pathway in SCLC and UBA1 may serve as a candidate biomarker and a potential mechanistic node for therapeutic intervention.