Abstract
BACKGROUND: The potential role of pyroptosis in tumor microenvironment (TME) reprogramming and immunotherapy has received increasing attention. As most studies have concentrated on a single TME cell type or a single pyroptosis regulator (PR), the overall TME cell-infiltrating characteristics mediated by the integrated roles of multiple PRs have not been comprehensively recognized. METHODS: This study curated 33 PRs and conducted consensus clustering to identify distinct pyroptosis patterns in gastric cancer (GC) patients. A single-sample gene set enrichment analysis algorithm was used to quantify the infiltration density of TME immune cells and the enrichment scores of well-defined biological signatures. The pyroptosis patterns of individuals were quantified using a principal component analysis algorithm called the pyroptosis score (PS). RESULTS: Three distinct pyroptosis patterns with significant survival differences were identified from 1422 GC samples; these patterns were closely associated with three TME cell-infiltrating landscapes-namely, the immune-inflamed, immune-excluded, and immune-desert phenotypes. The PS model generated on the basis of the pyroptosis pattern-related signature genes could accurately predict the TME status, existing molecular subtypes, genetic variation, therapeutic response, and clinical outcome; among which, a relatively high PS was highly consistent with immune activation, molecular subtypes with survival advantages, high tumor mutation burden, high microsatellite instability, and other favorable characteristics. In particular, from the Cancer Genome Atlas database, the PS model exhibited significant prognostic relevance in a pan-cancer analysis, and patients with a relatively high PS exhibited durable therapeutic advantages and better prognostic benefits in anti-PD1/L1 therapy. CONCLUSIONS: This study demonstrates that pyroptosis is prominently correlated with TME diversity and complexity, and quantification of the pyroptosis patterns of individuals will enhance our cognition of TME infiltration landscapes and help in formulating more effective immunotherapeutic strategies.