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Review
. 2025 Sep 15;85(18):3378-3398.
doi: 10.1158/0008-5472.CAN-24-3037.

Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts

Jacqueline M Flynn #  1 , Nikita Thadani #  1 , Erin E Gallagher #  1 , Isabella Azzaro #  1 , Cameron M Bodnar  2 , Colin P McCarty  2 , Gabriele Romano  3   4 , Marie R Webster  2   4 , Claudia Capparelli  1   4
Affiliations
Review

Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts

Jacqueline M Flynn et al. Cancer Res. .

Abstract

Tumor heterogeneity and plasticity enable adaptation to metastatic microenvironments and resistance to therapies. Recent progress in single-cell analyses has permitted detailed characterization of the complexity and diversity of the different tumor components in multiple tumor types. Cancer-associated fibroblasts (CAF) are a central component of the tumor microenvironment and play critical roles in cancer progression and therapeutic response. The identification of different CAF subtypes and elucidation of their functional plasticity are crucial for identifying novel therapeutic approaches to target protumorigenic CAFs and harness tumor-suppressive CAFs to enhance the efficacy of cancer treatments. In this review, we discuss how intrinsic and extrinsic factors and the extensive cross-talk between cancer cells and the tumor microenvironment promote CAF heterogeneity and their contributions to cancer progression and therapeutic resistance. Understanding the roles of CAF plasticity and their intercellular interactions may drive the development of effective treatment strategies to improve patient prognosis.

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Conflict of interest statement

Conflict of interest: No potential conflicts of interest were disclosed by any authors.

Figures

Figure 1.
Figure 1.. Omics analysis for CAF characterization.
Graphical representation of available technologies to detail CAF identity, functional properties, and spatial interactions. The main features of the represented technologies are labeled in red. Created in BioRender. Flynn, J. (2025) https://BioRender.com/fu3j89k
Figure 2.
Figure 2.. Overview of CAF subtypes.
A: Schematic showing cell(s) of origin, phenotype and/or function, markers and/or gene signature, and prognosis associated with each CAF subtype. B: Summary of CAF subtypes identified in different tumor types, markers and/or gene signature, and prognosis associated with each subtype. proCAF: progenitor CAF; myCAF: myofibroblast CAFs; senCAF: senescent CAF; mCAF: matrix-producing CAF; iCAF: inflammatory CAF; apCAF: antigen-presenting CAF; pan-dCAF: pan-desmoplastic CAF; pan-pCAF: pan-proliferating CAF ; CAFadi: adipogenic CAF; CAFpn: peripheral-nerve like CAF; ifnCAF: interferon-response CAF; rCAF: reticular-like CAF; tCAF: tumor-like CAF; csCAF: complement-secreting CAF; dCAF: developmental CAF; vCAF: vascular CAF; cCAF: cycling CAF; eCAF: EMT-like CAF. Created in BioRender. Flynn, J. (2025) https://BioRender.com/fu3j89k
Figure 3.
Figure 3.. Overview of major studies and findings from the “Cancer Cell State” section, focusing on cancer cell states and CAF heterogeneity.
Key mechanisms of crosstalk, including signaling pathways, molecular interactions, and spatial distribution influencing CAF function and plasticity in the tumor microenvironment. iCAF (inflammatory CAF), myCAF (myofibroblastic CAF), pan-pCAF (pan-proliferating CAF), pan-dCAF (pan-developmental CAF). Created in BioRender. Flynn, J. (2025) https://BioRender.com/fu3j89k
See this image and copyright information in PMC

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