Ma Lie, Han Yu, Chen Zixin, Liu Xuan, Wang Yu, Wang Zhiyao, Xiang Weifang, Li Lei, Jin Xin, Hou Jingyao, Li Yue, Huang Baiqu, Lu Jun, Zhang Yu
The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China.
School of life science, Northeast Normal University, Changchun 130024, China.
Sci Adv. 2025 Jul 11;11(28):eadw1553. doi: 10.1126/sciadv.adw1553.
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.
化疗诱导的不同细胞命运在癌症治疗结果中起着关键作用；然而，癌症复发期间细胞命运之间的相互作用仍不清楚。在此，我们发现从细胞衰老向细胞焦亡的转变促进了顺铂和依托泊苷治疗后小细胞肺癌（SCLC）的复发。化疗诱导的部分衰老SCLC细胞显示出阳性细胞质染色质片段（CCF），并且CCF激活了泛素编辑酶A20，A20通过其去泛素化活性稳定NLRP3，导致衰老细胞发生细胞焦亡。随后细胞焦亡释放的炎性因子[如白细胞介素-1（IL-1）]促进了CCF阴性衰老细胞中干细胞样特性的获得，最终促进肿瘤复发。我们还发现IL-1受体拮抗剂阿那白滞素与化疗联合使用可延迟SCLC的复发，这提示了此前未被发现的SCLC治疗策略。
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