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

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.