Transition of cellular senescence to pyroptosis mediates recurrence of small cell lung cancer after chemotherapy

  • Sci Adv. 2025 Jul 11;11(28):eadw1553. doi: 10.1126/sciadv.adw1553.
Lie Ma  1 ,  Yu Han  1 ,  Zixin Chen  2 ,  Xuan Liu  1 ,  Yu Wang  1 ,  Zhiyao Wang  1 ,  Weifang Xiang  2 ,  Lei Li  1 ,  Xin Jin  2 ,  Jingyao Hou  2 ,  Yue Li  3 ,  Baiqu Huang  1  2 ,  Jun Lu  1  2 ,  Yu Zhang  1  2
Affiliations
  • 1. The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China.
  • 2. School of life science, Northeast Normal University, Changchun 130024, China.
  • 3. Medical Oncology Department, Affiliated Tumor Hospital, Harbin Medical University, Harbin 150001, China.
PMID: 40644541 DOI: 10.1126/sciadv.adw1553
Abstract

Chemotherapy-induced different cell fates play crucial roles in Cancer treatment outcomes; however, the cross-talk between the cell fates during Cancer recurrence remains unclear. Here, we found that the transition from cellular senescence to Pyroptosis promoted small cell lung Cancer (SCLC) recurrence after cisplatin and etoposide treatment. Parts of the senescent SCLC cells induced by chemotherapy showed positive cytoplasmic chromatin fragments (CCFs), and CCFs activated the ubiquitin-editing enzyme A20, which stabilized NLRP3 through its deubiquitinating activity, resulting in senescent cells undergoing Pyroptosis. Subsequent inflammatory factors [such as interleukin-1 (IL-1)] released by Pyroptosis promoted the acquisition of stem-like properties in CCF-negative senescent cells, ultimately promoting tumor recurrence. We also found that a combination of IL-1 receptor antagonist anakinra with chemotherapy delayed recurrence of SCLC, suggesting previously unidentified therapeutic strategies for SCLC.

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