Fig. 1

Mechanisms of CRS. A. Cell interactions involved in CRS. Upon recognizing tumor antigens, CAR T-cells secrete perforin, granzyme and inflammatory cytokines, including IFN-γ and TNF-α, to induce pyroptosis of tumor cells, releasing large amounts of DAMPs that stimulate macrophages for massive cytokine production and CRS. Macrophages can also be activated by cytokines, such as GM-CSF, IFN-γ, TNF-α and catecholamine, or CD40/CD40L interactions with CAR T-cells. Pyroptosis of macrophages and further DAMPs leakage amplify the inflammatory cascade. IL-6 and other cytokines in CRS bind to their receptors on endothelial cells, causing an increase in vascular permeability and leakage and promoting cytokine production to exacerbate the CRS. B. Signaling pathway of pyroptosis in tumor cells. GZMA or GZMB enters tumor cells through perforin-induced pores. GZMB cleaves GSDME or activates caspase-3 to cleave GSDME. GZMA cleaves and activates GSDMB. Subsequently, the released gasdermin-N domain (N-GSDME or N-GSDMB) oligomerizes on the cell membrane to form membrane pores and disrupts the osmotic potential, resulting in cell swelling and lysis. C. Inflammatory signaling pathways in macrophages. Pyroptotic products include HMGB1, ATP, and dsDNA. HMGB1 activates TLR2 and TLR4 and subsequently recruits MyD88 and TRIF to activate MAPKs and IKK, leading to the subsequent production of inflammatory cytokines via AP-1 and NF-κB; ATP binds to the P2X7 receptor and induces NLRP3 activation; dsDNA is phagocytized by macrophages and activates AIM2. Activated AIM2 or NLRP3 combines with ASC and pro-caspase-1 to induce the maturation of caspase-1, which can cleave the N-terminus of GSDMD to form pores on the membrane, triggering pyroptosis and producing bioactive IL-1β. In addition, catecholamine can be recognized by α1-AR and activate the AIM2/ASC-caspase-1 pathway