ObjectiveTo identify key ligand-receptor axes that may improve immunotherapeutic strategies for hepatocellular carcinoma with portal vein tumor thrombus （PVTT）. MethodsSingle-cell RNA sequencing （scRNA-seq） data from normal tissues （Norm） and PVTT cells were downloaded from the gene expression omnibus （GEO） database， integrated， and annotated. CellChat was used to infer intercellular communication and compare pathway activities to screen significantly differential candidate ligand-receptor axes. Multiplex immunofluorescence （mIF） was then performed to evaluate the spatial distribution of signals related to candidate axes at the tissue level. The expression of key ligands and receptors was validated by qPCR and flow cytometry in peripheral blood-derived CD8⁺ T cells and the human hepatic stellate cell line LX-2. Functional effects were further assessed in vitro using recombinant proteins and antagonists or neutralizing blockers. ResultsThe analysis revealed strong bidirectional communication between CD8⁺ T cells and activated hepatic stellate cells （aHSCs） in PVTT. The SPP1-CD44 axis was the most prominent in the direction from CD8⁺ T cells to aHSCs， whereas the MIF-（CD74+ CD44） axis was strongly supported in the opposite direction. These axes were consistently supported by bioinformatic screening， tissue spatial analysis， and cellular or functional validation. ConclusionThe SPP1-CD44 and the MIF-（CD74+ CD44） axes may collectively shape the immunosuppressive tumor microenvironment （ITME） of PVTT through stromal activation and T-cell functional reprogramming， suggesting potential targets for improving immunotherapeutic responsiveness in patients with PVTT.