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

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.

A pyroptosis-related gene signature for prognosis prediction in hepatocellular carcinoma

“…The expression level of the 5 proteins in HCC. such as pyroptosis and immunization activities, have shown advantages in predicting the prognosis of HCC (12,(14)(15)(16)24). A robust prediction model may help improve outcomes of HCC patients.…”

“…HCC is the most common type of all primary liver cancer with a poor prognosis. Gene risk models based on specific cell activities, such as pyroptosis and immunization activities, have shown advantages in predicting the prognosis of HCC ( 12 , 14 – 16 , 24 ). A robust prediction model may help improve the outcomes of HCC patients.…”

“…GSDME may function as a tumor suppressor gene in HCC as its expression is significantly lower in HCC cells and upregulating GSDME expression inhibited cell proliferation. In HCC, numerous studies have also shown the functions of pyroptosis and the prognostic value of pyroptosis-related genes (PRGs) in HCC progression (12)(13)(14)(15)(16). Hence, PRGs may become the potential biomarkers to predict the prognosis of HCC and provide guidance for treatment.…”

Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy

“…Notably, nonstromal hepatocytes contribute significantly to shaping the tumor microenvironment, with macrophages attracting particular research interest. A study revealed a substantial association between pyroptosis and prognosis in HCC, suggesting that cellular pyroptosis-related genes contribute to the tumor microenvironment’s heterogeneity [ 127 ]. Utilizing in vivo macrophage depletion assays and in vitro analyses, researchers demonstrated the critical role of macrophages in mediating anti-tumor effects and identified a strong interdependence between macrophages and NK cells in efficiently eliminating tumor cells.…”