Dynamic subpopulations and spatial interactions of hepatic stellate cells and cancer-associated fibroblasts in liver cancer.

Liver cancer, especially hepatocellular carcinoma (HCC), has become a global health-care challenge due to its high incidence and extremely poor prognosis. The tumor microenvironment (TME) plays a crucial role in cancer initiation, progression and therapy resistance. Although combination immunotherapies have revolutionized the clinical management of advanced HCC, therapeutic resistance still develops in many patients, which is partially attributed to the immunosuppressive effects of hepatic stellate cells (HSCs) and/or cancer-associated fibroblasts (CAFs) and the physical matrix barrier they create. As major components of the TME, HSCs are a major source of CAFs in liver cancer, and they both engage in fibrogenesis and cancer progression. However, non-specific CAF-targeting strategies demonstrate limited efficacy owing to the heterogeneity of CAFs in terms of transcriptional programs, phenotypes and functions. Advances in single-cell and spatial multi-omics techniques not only reveal the heterogeneity and functions of various subgroups of HSCs and CAFs, but also delineate the integrative spatiotemporal regulatory landscape of HSCs and CAFs in the TME. In this review, we summarize the specific biomarkers and diverse functions of distinct HSC and CAF subpopulations in liver cancer, highlighting the transitions between different states and their driving signals. We also focus on the spatial distribution and cellular interactions of HSCs and CAFs with their neighboring cells in liver cancer revealed by spatial transcriptomics and proteomics. Collectively, these insights into HSCs and CAFs provide potentially feasible strategies to alleviate resistance to immune checkpoint inhibitors and offer potential novel targets for liver cancer treatment.