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

Pulmonary surfactant protein D (SP-D) is an endogenous innate immune factor known to be involved in several immune related diseases and has also been linked to lung adenocarcinoma cell growth. By analyzing single-cell, bulk, and spatial transcriptomics of human clinical samples, we have demonstrated significantly reduced expression in lung cancer cells compared to healthy cells, along with a distinct localization of SP-D expression in stromal areas adjacent to the tumor cells and at the periphery. Interestingly, a near-complete loss of SP-D expression was observed in metastatic tissue, suggesting its association with a more aggressive and metastatic phenotype. In this context, we show that SP-D re-expression in A549 adenocarcinoma cell line significantly decreased tumor growth and spontaneous metastasis formation in vivo and furthermore, that intranasal administration of recombinant SP-D signicantly reduced lung tumor burden. Mechanistically, we demonstrated that SP-D supresses interleukin 4 (IL4)/IL13 signaling pathways. Intriguingly, our data revealed that recombinant SP-D binds directly to the IL4 receptor, leading to the effective inhibition of the IL4 signaling pathway. Collectively, these findings demonstrate that SP-D acts as a tumor supressor inhibiting both tumor growth and metastatic progression potentially through blokage of the IL4/STAT6 signaling pathway. This provides a rationale of SP-D as a promising therapeutic agent for modulating crucial signaling pathways involved in cancer development and progression.