The role of CD93 in shaping the immune microenvironment and predicting immunotherapy response in advanced non-small cell lung cancer

Abstract In recent years, immunotherapy has substantially improved the clinical outcomes and survival benefits of patients with advanced non-small cell lung cancer (NSCLC). However, more than half of patients fail to achieve durable or clinically meaningful therapeutic responses. Therefore, identifying patients who are most likely to benefit from immunotherapy and enabling precision treatment remains a critical challenge in current clinical practice. Through integrated analyses of multiple public databases combined with validation using clinical specimens, we found that CD93 is predominantly expressed in endothelial cells and monocytes/macrophages, with endothelial cells exhibiting significantly higher CD93 expression levels compared with other CD93-positive cell populations. In lung cancer tissues, CD93 expression was positively associated with the infiltration of neutrophils, mast cells, and macrophages, while negatively associated with the infiltration of Th2 cells. These findings indicate that elevated CD93 expression in lung cancer tissues is correlated with reduced infiltration of effector immune cells and enhanced infiltration of immunosuppressive cell populations. Analysis of therapeutic efficacy demonstrated that patients with non-major pathological response (NMPR) exhibited higher average CD93 expression levels than those with major pathological response (MPR). Furthermore, patients with low CD93 expression tended to show more favorable overall survival (OS), particularly among individuals with lung adenocarcinoma. Consistently, patients with poor responses to immunotherapy exhibited relatively high CD93 expression in tumor tissues, whereas patients with favorable therapeutic response displayed lower CD93 expression levels. CD93-high lung cancer tissues displayed concomitantly low CD8 and high FOXP3 expression, while the opposite was observed in CD93-low tissues. Collectively, these findings may suggest that CD93 could contribute to the formation of an immunosuppressive microenvironment and might serve as a potential predictive biomarker for immunotherapy efficacy in patients with advanced NSCLC.