Introduction: The concept of the tumor microenvironment (TME), first introduced by Stephen Paget in 1889 through the “seed and soil” hypothesis, has recently received extensive attention based on accumulating evidence. Studies demonstrate that heterogeneous signaling among diverse cell types within a tumor creates a supportive environment that promotes cancer cell survival, proliferation, and immune evasion. Thus, cancer behavior depends not only on intrinsic defects of malignant cells but also on extrinsic factors, particularly the complex tumor microenvironment.
Methods: This abstract reviews articles published in 2022, 2023, and 2025. As will be discussed, cancer-associated fibroblasts (CAFs) consist of heterogeneous subpopulations, each with distinct roles such as tumor suppression or tumor promotion. Moreover, these cells exhibit plasticity, allowing interconversion between subtypes, which represents both a therapeutic opportunity and a challenge. Advances in single-cell RNA sequencing (scRNA-seq) and proteomics have enabled finer distinction of CAF subgroups, improving our understanding of their heterogeneity.
Results: As key stromal components, CAFs facilitate tumor growth, invasion, metastasis, and therapy resistance through interactions with cancer cells and remodeling of the extracellular matrix (ECM). Their crosstalk with signaling pathways, such as p53, and tumor epigenetic alterations can significantly influence tumor behavior and therapy response. CAFs originate from diverse sources, including resident fibroblasts, non-fibroblastic cells (epithelial, endothelial, adipocytes, pericytes, stellate, and mesothelial cells), and bone marrow–derived cells (e.g., mesenchymal stem cells and macrophages). This diversity underlies their phenotypic and functional heterogeneity. Major subgroups include:
myCAFs
iCAFs
apCAFs
Recently identified subgroups include vCAFs, cCAFs, dCAFs, LRRC15+ CAFs, and CD10+GPR77+ CAFs.
Conclusion: CAFs contribute to therapy resistance and tumor progression by inducing epithelial–mesenchymal transition (EMT) and secreting growth factors and cytokines. Their high plasticity, regulated by TGF-β and IL-6 signaling, allows interconversion between subtypes and offers therapeutic opportunities to reprogram them toward tumor-suppressive phenotypes. This paves the way for novel strategies combined with chemotherapy or immunotherapy.
A major challenge in targeting CAFs lies in their heterogeneity and dual role in tumor progression or suppression, which may result in unintended therapeutic outcomes. Ongoing phase I and II clinical trials are currently evaluating CAF-targeting drugs, emphasizing the importance of identifying specific CAF subsets for personalized treatment.
Technological advances, including scRNA-seq and proteomics, enable precise identification of CAF subgroups and key pathways. Novel therapeutic strategies include ECM modulation, selective elimination of protumorigenic CAFs, disruption of CAF–TME interactions, and normalization of CAF functions. A deeper understanding of CAF dynamics, plasticity, and genetic–epigenetic regulation offers a promising direction for next-generation stroma-targeted therapies and improved cancer treatment efficacy.