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Life sciences · Journal article
Frontiers in Immunology · September 22, 2026
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Hepatocellular carcinoma remains difficult to treat because immune resistance is organized not only by malignant cell states but also by the spatial architecture of the tumor microenvironment. Single-cell RNA sequencing has clarified cellular heterogeneity in liver cancer, yet tissue dissociation removes the positional relationships that determine whether immune cells can reach and eliminate tumor nests. Spatial transcriptomic, proteomic, and multiplex imaging technologies now make it possible to map immune exclusion, stromal barriers, vascular gatekeeping, tertiary lymphoid structures, macrophage and fibroblast programs, and metabolic checkpoints within intact tumor tissue. This review integrates recent single-cell and spatial multi-omics evidence to explain how suppressive neighborhoods emerge in hepatocellular carcinoma and how they shape immunotherapy response. We discuss the mechanisms through which malignant, myeloid, lymphoid, endothelial, and stromal populations interact across spatial niches, and we examine how these maps can inform biomarker discovery, patient stratification, and rational combination therapy. We also highlight limitations in cohort design, sampling depth, analytical integration, and clinical validation that currently constrain translation. By linking cellular states to their tissue coordinates, spatial omics provides a framework for understanding why ICI succeed in some tumors but fail in others. Integrating single-cell resolution with spatial context may help convert descriptive tumor atlases into clinically actionable maps for precision immuno-oncology.