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; Song Zhao; Sheng Wang; Lihua Liu

doi:10.1016/j.isci.2025.112321

Sleep deprivation-induced sympathetic activation promotes pro-tumoral macrophage phenotype via the ADRB2/KLF4 pathway to facilitate NSCLC metastasis

iScience. 2025 Mar 30;28(5):112321. doi: 10.1016/j.isci.2025.112321. eCollection 2025 May 16.

Authors

Shuxian Yin^{1

2}, Jiali Wang¹, Yunlong Jia¹, Xiaoyi Wang³, Yan Zhao¹, Tianxu Liu¹, Wei Lv¹, Yuqing Duan¹, Song Zhao⁴, Sheng Wang³, Lihua Liu^{1

5}

Affiliations

¹ Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Research Institute, Shijiazhuang, China.
² Hebei Key Laboratory of Stomatology, Hebei Technology Innovation Center of Oral Health, Hebei Medical University, Shijiazhuang, China.
³ Hebei Key Laboratory of Neurophysiology, Hebei Medical University, Shijiazhuang, China.
⁴ Department of Pathology, Hebei Medical University, Shijiazhuang, China.
⁵ International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, China.

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.

Keywords: Biological sciences; Cancer systems biology; Microenvironment; Natural sciences; Physiology; Systems biology.