Exploration of the Roles and Mechanisms Between Tumor‐Infiltrating Lymphocytes and Hepatocellular Carcinoma Based on Single‐Cell Transcriptomics

Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited effective treatment options, particularly in advanced‐stage patients. The tumor immune microenvironment (TIME) plays a crucial role in HCC progression and treatment response, with tumor‐infiltrating lymphocytes (TILs) being key modulators of immune activity. In this study, we investigated the immunosuppressive role of TIL‐related genes in NASH‐associated HCC (NASH‐HCC) and identified their potential as independent prognostic factors. We employed Gene Set Enrichment Analysis (GSEA) and Weighted Gene Coexpression Network Analysis (WGCNA) to explore immune suppression in NASH‐HCC and identify TIL‐related gene modules. Machine learning approaches were utilized to construct a prognostic model, validated using multiple cohorts from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The model’s predictive power was assessed using Kaplan–Meier survival analysis and receiver operating characteristic (ROC) curves. Furthermore, single‐cell RNA sequencing (scRNA‐seq) analysis was performed to examine the role of TIL‐related genes in different immune cell populations within TIME. We identified 10 distinct cell types in HCC and demonstrated that T cells exhibited the highest TIL pathway activity, playing a critical role in cellular communication via MIF signaling. Our findings highlight the immunosuppressive nature of TILs in NASH‐HCC and provide valuable insights into their prognostic significance, potentially guiding future immunotherapeutic strategies.