Photodynamic therapy induces human esophageal carcinoma cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis

Photodynamic therapy (PDT) uses a photosensitizer (PS) and visible LIGHT to induce Cancer cell death. Pyroptosis is a new type of programmed cell death that is associated with the gasdermin protein family. However, the precise mechanism of Pyroptosis in PDT-induced suppression of esophageal Cancer remains unknown. We demonstrate that PDT can induce gasdermin E (GSDME)-mediated Pyroptosis, which is characterized by the formation of pyroptotic blebs in esophageal squamous cell carcinoma (ESCC), which burst and release intracellular contents and pro-inflammatory mediators. Mechanistically, PDT may inhibit Pyruvate Kinase M2 (PKM2) and consequently, activate Caspase-8 and Caspase-3, which ultimately releases N-GSDME and triggers Pyroptosis in ESCC. Moreover, PDT decreased the efficiency of Pyroptosis in the presence of a glycolytic inhibitor. Overall, our results show that PDT induces Pyroptosis in ESCC by targeting the PKM2/Caspase-8/Caspase-3/GSDME axis. This is the first in-depth study of the specific mechanism underlying PKM2-mediated Pyroptosis under PDT in ESCC, and potentially has great implications for the clinical application of PDT in ESCC.