Background <p>CD4⁺ T cells, as critical mediators of immune regulation, have not been fully elucidated in their role in hepatocellular carcinoma (HCC) immune evasion.</p> Methods <p>We analyzed single-cell RNA sequencing (scRNA-seq) data from 16 HCC patients (GSE149614). Cell types were annotated based on cluster-specific differentially expressed genes (DEGs), utilizing the SingleR and PISCES for automated cell type assignment, with reference to established markers from previous studies. Metabolic reprogramming, transcriptional networks, and intercellular communication were assessed via GSVA, SCENIC, and CellChat. A prognostic model integrating TCGA-LIHC and validated in GSE109211 was developed using LASSO Cox regression. Molecular docking and dynamics simulations evaluated the therapeutic potential of prioritized targets.</p> Results <p>This study identifies SPP1⁺TNFRSF18⁺ CD4⁺ T cells as key drivers of HCC immune evasion. This subtype was enriched in tumor tissues, exhibited elevated immune checkpoint gene expression scores, and demonstrated metabolic reprogramming favoring tumor growth via glycolysis and reactive oxygen species (ROS) pathways. CellChat analysis revealed that SPP1-mediated interactions construct a multi-layered immunosuppressive network involving macrophages and CD8⁺ T cells. A prognostic model based on nine genes (<i>LIG1</i>,<i> NOP56</i>,<i> MIS18A</i>,<i> SMC4</i>,<i> CDCA8</i>,<i> DTYMK</i>,<i> ASF1B</i>,<i> RAD51</i>,<i> LGALS3</i>) was developed using TCGA-LIHC data and validated in an independent cohort (GSE109211), achieving robust predictive performance (AUC &gt; 0.7). Molecular docking and dynamics simulations confirmed the drug ability of these targets, which means these genes may serve as prognostic biomarkers and therapeutic targets.</p> Conclusions <p>Our findings establish SPP1⁺TNFRSF18⁺ CD4⁺ T cells as central regulators of HCC immune suppression, offering novel strategies to enhance HCC immunotherapy.</p> Graphical abstract <p></p>