Sleep deprivation-induced sympathetic activation promotes pro-tumoral macrophage phenotype via the ADRB2/KLF4 pathway to facilitate NSCLC metastasis
Shuxian Yin, Jiali Wang, Yunlong Jia, Xiaoyi Wang, Yan Zhao, Tianxu Liu, Wei Lv, Yuqing Duan, Zhao Song, Sheng Wang, Lihua Liu
Abstract
Sleep deprivation is one of concomitant symptoms of cancer patients, particularly those with non-small cell lung cancer (NSCLC). The potential effect of sleep deprivation on tumor progression and underlying mechanisms remain to be fully investigated. Using a sleep-deprived tumor-bearing mouse model, we found that sleep deprivation altered immune cell composition and regulated pro-tumoral M2 macrophage polarization by the sympathetic nervous system. Furthermore, we identified a role of catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) in influencing NSCLC metastasis. Clinical analyses revealed a correlation between sympathetic-related indicators and poor prognosis. Mechanistically, our findings indicate that sleep deprivation facilitates the polarization of pro-tumoral macrophages by upregulating β2-adrenergic receptor (ADRB2), which subsequently enhances the expression of Kruppel-like transcription factor 4 (KLF4) through the JAK1/STAT6 phosphorylation pathway. These findings highlight a neuro-immune mechanism linking sleep deprivation to NSCLC metastasis, suggesting that targeting the ADRB2/KLF4 axis could improve outcomes for sleep-deprived NSCLC patients.