Integrative bibliometrics and spatial transcriptomics identify CAF-associated genes and immune niches in hepatocellular carcinoma.

[BACKGROUND] Cancer-associated fibroblasts (CAFs), as a major stromal component of the tumor microenvironment (TME) in hepatocellular carcinoma (HCC), play critical roles in regulating tumor progression, immune evasion, and therapeutic responses. However, research on CAFs in HCC remains fragmented, and systematic synthesis with multidimensional mechanistic integration is still lacking.

[OBJECTIVE] This study aims to systematically elucidate the key roles and mechanisms of CAFs in therapeutic resistance, metastasis, and immune microenvironment remodeling in HCC by integrating bibliometric analysis with multi-omics and spatial transcriptomic data.

[METHODS] Original research articles related to CAFs and HCC were systematically retrieved from the Web of Science Core Collection. Bibliometric analyses were conducted using the R package Bibliometrix to assess annual publication trends, country- and institution-level collaboration networks, author and journal distributions, and keyword evolution patterns. In addition, transcriptomic datasets from GEO, TCGA, and ICGC, together with spatial transcriptomic data, were integrated to identify CAF-related differentially expressed genes, characterize their spatial localization, and evaluate correlations between CAF-related gene expression and immune cell infiltration, thereby exploring their potential biological functions.

[RESULTS] A total of 266 original studies were included. Since 2018, publications in the CAF–HCC field have increased markedly, accompanied by expanding international collaboration. Keyword analyses indicated that “resistance,” “metastasis,” “tumor microenvironment,” and “immune regulation” have remained central research themes. Mechanistic integration suggested that CAFs promote HCC stemness maintenance, immunosuppression, and pre-metastatic niche formation via pathways including TGF-β, IL-6/STAT3, and VEGFA. Multi-omics analyses identified 34 key genes commonly upregulated in both CAFs and HCC tissues. Spatial transcriptomic profiling further revealed that MMP9, SPP1, MMP12, and TREM2 exhibited pronounced spatial enrichment in tumor core regions and the tumor–stroma interface, with significant co-localization with immune cells such as macrophages and regulatory T cells. Among these, TREM2 showed the strongest positive correlation with macrophage infiltration, suggesting a potential role in CAF–immune cell crosstalk and the establishment of an immunosuppressive microenvironment in HCC.

[CONCLUSION] CAFs exert multilayered and dynamic regulatory effects on therapeutic resistance, metastasis, and immune microenvironment remodeling in HCC.