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-alpha. 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-alpha 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.
[1]Tianjin Med Univ Gen Hosp, Dept Lung Canc Surg, Tianjin 300052, Peoples R China.
[2]Tianjin Med Univ Canc Inst & Hosp, Dept Esophagus Surg,Key Lab Digest Canc Tianjin, Tianjins Clin Res Ctr Canc, Natl Clin Res Ctr Canc, Tianjin 300060, Peoples R China.
[3]Tianjin Med Univ Gen Hosp, Tianjin Lung Canc Inst, Tianjin Key Lab Lung Canc Metastasis & Tumor Micro, Tianjin 300052, Peoples R China.
(8.0+极速模式)