Architectural Regulation of T‐Lymphocyte Function in Hepatocellular Carcinoma: Current Evidence and Translational Opportunities

ABSTRACT 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.