Comprehensive characterization of pyroptosis phenotypes with distinct tumor immune profiles in gastric cancer to aid immunotherapy

Objective: Pyroptosis is a form of programmed cell death that is essential for immunity. Herein, this study was conducted to uncover the implication of pyroptosis in immunomodulation and tumor microenvironment (TME) in gastric cancer. Methods: Prognostic pyroptosis-related genes were extracted to identify different pyroptosis phenotypes and pyroptosis genomic phenotypes via unsupervised clustering analysis in the gastric cancer meta-cohort cohort (GSE15459, GSE62254, GSE84437, GSE26253 and TCGA-STAD). The activation of hallmark gene sets was quantified by GSVA and immune cell infiltration was estimated via ssGSEA and CIBERSORT. Through PCA algorithm, pyroptosis score was conducted. The predictors of immune response (TMB and IPS) and genetic mutations were evaluated. The efficacy of pyroptosis score in predicting immune response was verified in two anti-PD-1 therapy cohorts. Results: Three different pyroptosis phenotypes with different prognosis, biological pathways and tumor immune microenvironment were established among 1275 gastric cancer patients, corresponding to three immune phenotypes: immune-inflamed, immune-desert, and immune-excluded. According to the pyroptosis score, patients were separated into high and low pyroptosis score groups. Low pyroptosis score indicated favorable survival outcomes, enhanced immune responses, and increased mutation frequency. Moreover, low pyroptosis score patients displayed more clinical benefits from anti-PD-1 and prolonged survival time. Conclusion: Our findings uncovered a nonnegligible role of pyroptosis in immunomodulation and TME multiformity and complicacy in gastric cancer. Quantifying the pyroptosis score in individual tumors may tailor more effective immunotherapeutic strategies.