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Review
. 2025 Oct 8;24(1):250.
doi: 10.1186/s12943-025-02461-0.

Emerging role of cancer-associated fibroblasts in the premetastatic niche

Shuaixi Yang #  1 , Ying Guo #  2 , Jiachi Jia #  2 , Wenming Cui  1 , Xinhao Zhang  1 , Yuhang Wang  1 , Zhiyuan Xie  2 , Yingshuai Fang  2 , Xianfei Ding  3 , Lei Chang  4 , Ying Liu  5
Affiliations
Review

Emerging role of cancer-associated fibroblasts in the premetastatic niche

Shuaixi Yang et al. Mol Cancer. .

Abstract

In recent years, tumor metastasis has become one of the major causes of high recurrence and mortality in cancer patients. Owing to multiorgan involvement, metastatic cancers are now clinically difficult to cure and often have a very poor prognosis. In recent years, an increasing number of studies have shown that the establishment of a premetastatic niche (PMN) is necessary for tumor metastasis. Cancer-associated fibroblasts (CAFs), which are closely related to tumor development, are deeply involved in regulating PMN establishment. By regulating EVs, metabolism and other pathways, CAFs actively shape microenvironmental characteristics, including inflammation, angiogenesis, increased vascular permeability, lymphangiogenesis, immunosuppression and extracellular matrix (ECM) remodeling. With the development of single-cell sequencing technology, our understanding of the role and significance of heterogeneous CAFs in the PMN has improved. Multiple therapeutic strategies targeting CAFs in the PMN have also been developed. This article focuses on the crosstalk of different subtypes of CAFs with other stromal cells, the mechanisms by which CAFs of different origins mediate PMN formation, and the emerging cancer therapeutic strategies by which CAFs have been targeted in recent years.

Keywords: Cancer-associated fibroblasts; Premetastatic niche; Treatments; Tumor metastasis.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Cellular origin of CAFs. The major cellular sources of CAFs include quiescent fibroblasts and stellate cells (by activation), macrophages (by MMT), epithelial cells (by EMT), endothelial cells (by EndMT), and MSCs (by recruitment and EMT), as well as pericytes, smooth muscle cells, and adipocytes (by transdifferentiation).
Fig. 2
Fig. 2
Briefly summarize the important factors recently identified to be involved in CAF activation, as explained separately in the text: TDSFs (A); EVs (B); and stressors in the local microenvironment (C).
Fig. 3
Fig. 3
Briefly, recent progress in understanding the dynamic crosstalk between different subtypes of CAFs and other stromal cells, which are explained in the text: iCAFs (A); mCAFs (B); apCAFs (C); tCAFs (D); and vCAFs (E)
Fig. 4
Fig. 4
Characteristics of the premetastatic niche formed by CAF involvement: inflammation (A); angiogenesis (B); lymphangiogenesis (C); immunosuppression (D); and ECM remodeling (E)
Fig. 5
Fig. 5
Treatments targeting CAFs, which are explained in the text: CAF depletion (A); targeting CAF activation (B); inhibiting CAF function (C)
See this image and copyright information in PMC

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