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Review
. 2025 Feb;15(2):e70224.
doi: 10.1002/ctm2.70224.

Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone

Jiayan Yan  1   2   3 , Zhifeng Jiang  1   2   3 , Shiyu Zhang  1   2   3 , Qichao Yu  4   5 , Yijun Lu  1   2   3 , Runze Miao  1   2   3 , Zhaoyou Tang  1   2 , Jia Fan  1   2 , Liang Wu  5 , Dan G Duda  6 , Jian Zhou  1   2 , Xinrong Yang  1   2
Affiliations
Review

Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone

Jiayan Yan et al. Clin Transl Med. 2025 Feb.

Abstract

Solid tumours are intricate and highly heterogeneous ecosystems, which grow in and invade normal organs. Their progression is mediated by cancer cells' interaction with different cell types, such as immune cells, stromal cells and endothelial cells, and with the extracellular matrix. Owing to its high incidence, aggressive growth and resistance to local and systemic treatments, liver cancer has particularly high mortality rates worldwide. In recent decades, spatial heterogeneity has garnered significant attention as an unfavourable biological characteristic of the tumour microenvironment, prompting extensive research into its role in liver tumour development. Advances in spatial omics have facilitated the detailed spatial analysis of cell types, states and cell‒cell interactions, allowing a thorough understanding of the spatial and temporal heterogeneities of tumour microenvironment and informing the development of novel therapeutic approaches. This review illustrates the latest discovery of the invasive zone, and systematically introduced specific macroscopic spatial heterogeneities, pathological spatial heterogeneities and tumour microenvironment heterogeneities of liver cancer.

Keywords: immunosuppression; invasive zone; liver cancer; spatial heterogeneity; tumour microenvironment.

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Conflict of interest statement

The authors declare they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram of the workflow of spatial transcriptomics acquisition of liver cancer, margin area profiling and further data analysis.
FIGURE 2
FIGURE 2
Local ecosystem of the invasive zone in liver cancers.
FIGURE 3
FIGURE 3
Macroscopic features of spatial heterogeneity in liver cancer.
FIGURE 4
FIGURE 4
Pathological features of spatial heterogeneity in liver cancer.
FIGURE 5
FIGURE 5
Spatial heterogeneity of immune cell components in tumour microenvironment (TME) of liver cancer.
FIGURE 6
FIGURE 6
Cellular components and tumour‐infiltrating lymphocyte (TIL)‐multiplexed Immunofluorescence (IF) staining.
FIGURE 7
FIGURE 7
Maturity of tumour‐infiltrating lymphocyte (TIL) and their cellular components.
FIGURE 8
FIGURE 8
Temporal heterogeneity of liver cancers.
FIGURE 9
FIGURE 9
Role of spatial and temporal heterogeneities of liver cancer in the clinical application.
See this image and copyright information in PMC

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