Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment

Jingjuan Zhu; Xiao Xu; Man Jiang; Fangfang Yang; Yingying Mei; Xiaochun Zhang

doi:10.3389/fonc.2023.1145380

Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment

Front Oncol. 2023 Mar 27:13:1145380. doi: 10.3389/fonc.2023.1145380. eCollection 2023.

Authors

Jingjuan Zhu^{1

2}, Xiao Xu^{1

2}, Man Jiang¹, Fangfang Yang², Yingying Mei², Xiaochun Zhang¹

Affiliations

¹ Cancer Precision Medical Center, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.
² Qingdao Medical College, Qingdao University, Qingdao, China.

Abstract

Background: Ferroptosis is a type of regulatory cell death (RCD) mode that depends on iron-mediated oxidative damage. It has the potential to improve the efficacy of tumor immunotherapy by modulating the tumor microenvironment (TME). Currently, immunotherapy has significantly improved the overall treatment strategy for advanced hepatocellular carcinoma (HCC), but the distinct immune microenvironment and high tolerance to the immune make massive differences in the immunotherapy effect of HCC patients. As a result, it is imperative to classify HCC patients who may benefit from immune checkpoint therapy. Simultaneously, the predictive value of ferroptosis in HCC and its potential role in TME immune cell infiltration also need to be further clarified.

Methods: Three ferroptosis molecular models were built on the basis of mRNA expression profiles of ferroptosis-related genes (FRGs), with notable variations in immunocyte infiltration, biological function, and survival prediction. In order to further investigate the predictive impact of immunotherapy response in HCC patients, the ferroptosis score was constructed using the principal component analysis (PCA) algorithm to quantify the ferroptosis molecular models of individual tumors.

Results: In HCC, there were three totally different ferroptosis molecular models. The ferroptosis score can be used to assess genetic variation, immunotherapy response, TME characteristics, and prognosis. Notably, tumors with low ferroptosis scores have extensive tumor mutations and immune exhaustion, which are associated with a poor prognosis and enhanced immunotherapy response.

Conclusions: Our study indicates that ferroptosis plays an indispensable role in the regulation of the tumor immune microenvironment. For HCC, the ferroptosis score is an independent prognostic indicator. Assessing the molecular model of ferroptosis in individual tumors will assist us in better understanding the characteristics of TME, predicting the effect of immunotherapy in HCC patients, and thus guiding a more reasonable immunotherapy program.

Keywords: ferroptosis; hepatocellular carcinoma; immunotherapy; molecular typing; prognosis; tumor microenvironment.

Grants and funding

Funding for this research was provided by the Qingdao Key Discipline Foundation; Shandong Health Science and technology development foundation (202102040497).