Architectural Regulation of T-Lymphocyte Function in Hepatocellular Carcinoma: Current Evidence and Translational...

Hepatocellular carcinoma (HCC) develops within a chronically injured liver in which anti-tumor immunity is governed not only by immune-cell abundance and checkpoint signaling, but also by the spatial, mechanical, and multicellular organization of T lymphocytes. This review reframes T-cell architecture as a regulatory layer operating across molecular, cellular, and tissue scales. Cytoskeletal remodeling, immunological synapse geometry, mechanotransduction, vascular positioning, stromal exclusion, and tertiary lymphoid structure (TLS) organization collectively influence T-cell activation thresholds, effector competence, exhaustion trajectories, and therapeutic responsiveness. We synthesize HCC-specific evidence from spatial transcriptomics, multiplex imaging, digital pathology, and clinical cohorts, while clearly distinguishing direct HCC observations from mechanisms extrapolated from other solid tumors or foundational T-cell biology. Current evidence supports the prognostic relevance of intratumoral CD8+ localisation, perivascular immune rims, fibrotic exclusion niches, and mature intratumoral TLS, but causal links between architecture and T-cell fate remain incompletely defined. We propose an architecture-guided framework in which spatial immune states serve as both biomarkers and modifiable therapeutic targets. Spatially informed checkpoint blockade, engineered T-cell therapy, stromal and vascular remodeling, AI-assisted pathology, and organoid or liver-on-chip models may enable more precise immunotherapy strategies for HCC.