Pulmonary surfactant protein D reduces lung cancer progression associated with decreased IL-4/STAT6 signaling

Pulmonary surfactant protein D (SP-D) is an innate immune molecule implicated in lung cancer, where its expression correlates with improved survival and reduced tumor growth. Despite its relevance to lung pathobiology, the transcriptional programs regulated by SP-D and their role in cancer progression and metastasis remain poorly understood. Through integrative analysis of multimodal human data we demonstrate that the SP-D gene (SFTPD) expression is reduced to near absence in metastatic non-small cell lung cancer (NSCLC) tissue, linking its loss to metastatic progression. SFTPD overexpression in A549 lung adenocarcinoma cells significantly decreased tumor growth and metastasis in vivo, and intranasal SP-D protein administration reduced lung tumor burden. Mechanistically, SP-D suppressed several signaling pathways, including IL-4/STAT6 signaling. Analysis of clinical lung tumor samples confirmed that SFTPD expression is associated with reduced IL-4/STAT6 signaling, and patients with low SFTPD expression and elevated IL-4 signaling in their tumors showed the poorest disease-free survival. Our findings demonstrate that SP-D interacts with NSCLC cells to suppress lung cancer progression, in part by blocking of the IL-4/STAT6 signaling pathway.