Novel Risk Classification Based on Pyroptosis-Related Genes Defines Immune Microenvironment and Pharmaceutical Landscape for Hepatocellular Carcinoma

SIMPLE SUMMARY: It has been indicated that pyroptosis functions in the development of cancer as well as the orchestration of cancer cell death. Nonetheless, specific roles of pyroptosis-related genes in tumor progression, immune response, prognosis and immunotherapy have, to date, not been thoroughly elucidated. After a comprehensive evaluation of pyroptosis patterns, unsupervised clustering was performed to generate three distinct clusters of 26-gene profiles from HCC. We aimed to establish an efficiency criterion for classifying and predicting patients’ prognosis. After comprehensive analysis of the clustering and risk scoring system, satisfactory sensitivity and specificity are demonstrated, and new insights into the molecular characterization of pyroptosis-related subtypes are contributed. ABSTRACT: Growing evidence has indicated that pyroptosis functions in the development of cancer. Nonetheless, specific roles of pyroptosis-related genes in tumor progression, immune response, prognosis, and immunotherapy have not been thoroughly elucidated. After a comprehensive evaluation of pyroptosis genes, unsupervised clustering was performed to generate three distinct clusters from hepatocellular carcinoma (HCC) samples. Three distinct pyroptosis-related molecular subtypes comprising three gene clusters that had differential prognostic effects on patient survival were then identified. Immune characteristics analyses revealed diversified immune cell infiltration among the subtypes. Two clusters served as immune-hot phenotypes associated with significantly poorer survival compared to a remaining third immune-cold cluster. Among these, the immune-hot clusters were characterized by abundant adaptive immune cell infiltration, active CD4+ and CD8+ T cells, high total leukocyte counts and tumor growth status, and lower Th17 cell and M2 macrophage densities. Then, risk scores indicated that low-risk patients were more sensitive to anti-tumor therapy. Subsequently, we found a significant correlation between pyroptosis and prognosis in HCC and that pyroptosis genes drive the heterogeneity of the tumor microenvironment. The risk scoring system, based on pyroptosis-related differentially expressed genes, was established to evaluate the individual outcomes and contribute to new insights into the molecular characterization of pyroptosis-related subtypes.