Fig. 4

Other pathways of pyroptosis. In the caspase-3/8-mediated pathway, the inhibition of TAK1 activates caspase-8, resulting in GSDMD cleavage and pyroptosis. With the help of p-Stat3, PD-L1 is transferred to the nucleus and upregulates the transcription of GSDMC under hypoxia conditions. Activated by TNF-α, caspase-8 specifically cleaves GSDMC into GSDMC-N and eventually forms pores on the cell membrane, causing cell swelling, lysis and death. Chemotherapeutic drugs could induce caspase-3-mediated GSDME cleavage with high GSDME expression and form N-GSDME termini, which caused pyroptosis of tumor cells. In the granzyme-mediated pathway, CAR-T cells activate caspase-3 in target cells and release GzmB, causing GSDME-mediated pyroptosis, while GzmA secreted from CD8⁺ T cells and NK cells induces GSDMB-mediated pyroptosis