Integrative Profiling of Metabolic CYP Expression, DNA Mutation Rates, and Immune Cell Infiltration for Survival Prognosis in Hepatocellular Carcinoma

Background/Objectives: Hepatocellular carcinoma (HCC) is challenging to treat with chemotherapy. Immunotherapy has shown moderate responses in inflammatory and immunosuppressive tumor environments. Hepatic cytochrome P450 monooxygenases (CYPs) play a crucial role in xenobiotic and drug metabolism, as well as lipid and steroid metabolism. We aimed to investigate whether CYP expression and various parameters of the innate and adaptive immune system are prognostic factors for the survival of HCC patients. Methods: HCC biopsies (n = 370) from The Cancer Genome Atlas (TCGA) database were analyzed using Kaplan–Meier statistics and the KMPlotter algorithm. Parameters such as immune cell infiltration, DNA mutation rates, and neoantigen load were selected for survival analysis and subjected to hierarchical cluster analysis. The expression of candidate CYP genes in tumors was compared to that in normal liver tissues. Furthermore, tumor infiltration of innate immune cells (basophilic and eosinophilic granulocytes, natural killer cells), adaptive immune cells (CD4+ memory and CD8+ cytotoxic T cells, regulatory T cells, type 1 and type 2 helper T cells), and mesenchymal stem cells was examined. Results: High expression of CYP19A1 and CYP26B1 was associated with shorter survival, whereas high expression of CYP3A5, CYP3A43, CYP7A1, and CYP27A1 was linked to longer survival. Mutation rates combined with CYP expression showed a correlation with five out of six CYP genes, while a high neoantigen load produced less definitive results. A specific cluster exhibiting high CYP expression and immune cell counts or mutation/neoantigen rates was associated with shorter survival, while another cluster was linked to longer survival. Conclusions: CYPs involved in the metabolic regulation of HCC, including CYP3A5, CYP3A43, CYP7A1, CYP19A1, CYP26B1, and CYP27A1, were found to have prognostic value for patient survival. Combined signatures that include CYP expression, mutational rates, and immune cell infiltration into tumors further enhanced the prognostic value for patient survival. This suggests that CYPs may influence the creation of a tumor-specific metabolic microenvironment that impacts immune functions. These combined signatures could be utilized for patient stratification to personalize tumor treatment and develop novel combination therapies aimed at optimizing treatment outcomes, such as combining transarterial chemoembolization (TACE) with immune checkpoint inhibitors.