Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps

Dasa He; Qiuyao Wu; Pu Tian; Yin Liu; Zhenchang Jia; Zhenwei Li; Yuan Wang; Yuchen Jin; Wenqian Luo; Ling Li; Peiyuan Zhang; Qianlu Jin; Wenjing Zhao; Weiguo Hu; Yajun Liang; Bin Zhou; Qifeng Yang; Yi-Zhou Jiang; Zhi-Ming Shao; Guohong Hu

doi:10.1016/j.ccell.2025.06.007

Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps

Cancer Cell. 2025 Jun 24:S1535-6108(25)00257-0. doi: 10.1016/j.ccell.2025.06.007. Online ahead of print.

Authors

Dasa He¹, Qiuyao Wu¹, Pu Tian¹, Yin Liu², Zhenchang Jia¹, Zhenwei Li¹, Yuan Wang¹, Yuchen Jin¹, Wenqian Luo¹, Ling Li³, Peiyuan Zhang¹, Qianlu Jin¹, Wenjing Zhao⁴, Weiguo Hu³, Yajun Liang¹, Bin Zhou⁵, Qifeng Yang⁴, Yi-Zhou Jiang², Zhi-Ming Shao², Guohong Hu⁶

Affiliations

¹ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
² Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
³ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁴ Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan 250012, China.
⁵ Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁶ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: ghhu@sinh.ac.cn.

PMID: 40614736
DOI: 10.1016/j.ccell.2025.06.007

Abstract

Disseminated tumor cells (DTCs) can remain in a non-proliferative, dormant state for years in distant organs, but the exogenous causes triggering their reactivation and metastatic colonization are unclear. Here, we demonstrate that chemotherapeutic drugs, including doxorubicin and cisplatin, enhance proliferation and lung metastasis of dormant breast cancer cells. Using a recombinase-based dormancy tracing system, DormTracer, we confirm chemotherapy-induced reactivation of dormant DTCs leading to metastatic relapse. Mechanistically, chemotherapy induces fibroblast senescence, which promotes formation of neutrophil extracellular traps (NETs) through secreted proteins. NETs promote dormant DTC proliferation through extracellular matrix remodeling. Importantly, combining senolytic drugs, dasatinib and quercetin, with doxorubicin inhibits post-therapy DTC reactivation and suppresses metastatic relapse. This study provides direct evidence of dormancy awakening and reveals a mechanism underlying detrimental effect of chemotherapy on metastasis, highlighting potential strategies to improve cancer treatment.

Keywords: chemotherapy; dormancy awakening; metastatic dormancy; neutrophil extracellular trap.