Integrative Analysis of Fatty Acid Metabolism, Intratumor Microbiota and Tumor Phenotypes in Hepatocellular Carcinoma

Fatty acid metabolism (FAM) plays a critical role in cancer development and progression, especially in hepatocellular carcinoma (HCC), as the liver is an important site of FAM. However, the associations of FAM with the tumor microenvironment and tumor phenotypes in HCC have not been fully elucidated. Here, we retrospectively obtained bulk RNA-seq and single-cell RNA sequencing data, intratumoral microbiome data and immune response data from HCC patients. Patients with activation of the FAM pathway exhibited elevated tumor purity, increased tumor mutational burden and a poor response to immunotherapy. Based on FAM-related genes, we constructed a robust machine learning framework combining least absolute shrinkage and selection operator (Lasso) and partial least squares Cox regression (PlsRcox) to predict survival; its performance was validated using multiple independent datasets. Single-cell sequencing revealed that risk scores were increased in malignant cells and tumor-associated macrophages. Furthermore, associations between FAM and the intratumoral microbiota were detected, and we constructed a biological network linking specific genera, immune cells and FAM-related genes. These findings provide a clinically applicable prognostic tool and highlight FAM and the intratumoral microbiota as promising therapeutic targets to improve HCC treatment, particularly for immunotherapy-resistant patients.