GSDME-mediated pyroptosis modulates the immunosuppressive microenvironment in lung adenocarcinoma.

Despite the increasing recognition of pyroptosis, particularly that involving GSDME, its precise impact on tumor prognosis and the immune microenvironment remains elusive, necessitating a comprehensive investigation in the context of lung adenocarcinoma (LUAD). We aimed to construct a pyroptosis-related prognostic model and to elucidate the intricate dynamics of GSDME-mediated pyroptosis in shaping tumor immunity in LUAD. We developed a pyroptosis-related prognostic model using machine learning. GSDME-mediated pyroptosis in LUAD cells was induced using CHX and TNF-α. HMGB1 content in the cell supernatant after cell pyroptosis and in serum from patients before treatment with PD-1/PD-L1 antibodies was determined by Enzyme-Linked Immunosorbent Assay. In vivo, Lewis lung carcinoma (LLC)-bearing C57 mice were treated with cisplatin and/or caspase-3 inhibitors, anti-PD-1, and IL-8 inhibitors, with tumor growth monitored. Our prognostic prediction model (PYR_score), built upon pyroptosis-related genes, demonstrated high efficacy in predicting LUAD prognosis across diverse datasets. Machine learning analyses revealed that higher PYR_score values correlated with shorter progression-free and overall survival. CHX and TNF-α induced GSDME-mediated pyroptosis with elevated HMGB1. Increased HMGB1 was associated with worse therapeutic efficacy of immune checkpoint inhibitors in LUAD patients. HMGB1 increased the proliferative ability and IL-8 secretion of Treg cells in vitro. Caspase-3 and IL-8 inhibitors slowed tumor growth, and IL-8 inhibitors possibly enhanced the effectiveness of anti-PD-1 immunotherapy in LLC-bearing mice. In summary, our novel PYR_score is a robust prognostic marker, offering predictive power across different datasets. GSDME-mediated pyroptosis modulated the immunosuppressive microenvironment via elevations in HMGB1, Treg cells, and MDSCs. IL-8 inhibitors may inhibit Tregs and MDSCs and enhance the effectiveness of anti-PD-1 immunotherapy. Further clinical validation and exploration of therapeutic interventions targeting these pathways are essential for translating these findings into clinical practice.