Cancer-associated fibroblasts as a potential therapeutic target for thyroid cancers

Abstract

Thyroid cancer, a prevalent endocrine malignancy, is influenced by its tumor microenvironment (TME), with cancer-associated fibroblasts (CAFs) playing a pivotal role in disease progression. Molecularly, CAFs orchestrate a pro-tumorigenic niche via cytokine secretion and extracellular matrix (ECM) stiffening, underscoring their targetability. Therapeutic strategies, including small molecule inhibitor-based therapies, immune-based therapies, nanoparticle-based approaches, and combination regimens, have been evaluated for their efficacy in disrupting CAF functionality. CAFs from resident fibroblasts or recruited precursors can promote the progression of thyroid cancer through ECM remodeling, angiogenesis, and epithelial-mesenchymal transition (EMT) induction while facilitating immune evasion. These processes can enhance tumor invasiveness, metastasis, and resistance to conventional therapies. Preclinical studies using thyroid cancer models have demonstrated promising outcomes, such as reduced tumor burden and enhanced drug sensitivity upon CAF inhibition. Emerging clinical trials have tested CAF-directed agents in patient cohorts and validated these findings. However, many challenges persist, including the identification of reliable CAF-specific biomarkers, optimization of treatment timing, and integration of the biomarkers into personalized medicine frameworks. This review explores the therapeutic potential of CAFs for thyroid cancers, emphasizing their origin, activation, and multifaceted contributions to tumor growth. This review synthesizes current evidence, highlighting CAFs as a novel therapeutic frontier for thyroid cancers. Future research should focus on refined biomarker discovery and strategic therapeutic sequencing to maximize clinical benefits, providing a roadmap for translating CAF-targeted approaches into effective treatments for thyroid cancers.

Keywords: cancer-associated fibroblast; epithelial–mesenchymal transition; extracellular matrix; inhibitor; thyroid cancer.

Figure 1.

Thyroid cancer overview (created in https://BioRender.com).

Figure 2.

Progression from normal thyroid fibroblasts to thyroid cancer-associated fibroblasts (created in https://BioRender.com). FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TNF, tumor necrosis factor.

Figure 3.

Crosstalk between cancer-associated fibroblasts (CAFs) and immune cells in the tumor microenvironment (TME). CAFs promote an immunosuppressive TME by secreting factors (such as TGF-β, IL-6, CXCL12, and VEGF) that exhibit the following effects: (A) Polarize immune cells (TAMs, TANs, DCs, and T cells) into pro-tumorigenic subtypes. (B) Recruit and activate immunosuppressive cells (M2-TAMs, N2-TANs, Tregs, and MDSCs). (C) Suppress cytotoxic NK cells and CTLs. (D) Upregulate immune checkpoints (PD-1/PD-L1 and CTLA-4). (E) Remodel the ECM (via collagen, MMPs, and FAK) to hinder immune function. Reciprocally, immune cells (TAMs, TANs, and DCs) enhance CAF activation, creating an immunosuppressive loop. In thyroid cancer, CAFs prominently drive the polarization of TAMs to the M2 subtype and recruit Tregs via TGF-β and CXCL12 signaling, contributing to therapy resistance and immune escape (adapted with permission from Biffi and Tuveson^[48] Copyright © 2021, The Author(s) CC-BY 4.0 International License). DC, dendritic cell; IL, interleukin; MMP, matrix metalloproteinase; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-L1, programmed death ligand 1; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TGF-β, transforming growth factor-beta; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

Figure 4.

Strategies for targeting CAFs. CAFs can be depleted by several treatments targeting CAF-specific markers, such as FAP and α-SMA. The normalization of CAFs from a pro-tumorigenic state to a quiescent or tumor-suppressive state can also be used for cancer treatment with small molecules, such as ATRA or VDR ligands. The key signaling agents driving the tumor-promoting function of CAFs, e.g., cytokines and growth factors, can be targeted to inactivate CAFs. Finally, CAF-derived ECM proteins or related signaling agents can be targeted to induce ECM remodeling (adapted with permission from Gallego-Rentero et al^[117], Copyright © 2023, The Author(s) CC-BY 4.0 International License). α-SMA, α-smooth muscle actin; ATRA, All-trans retinoic acid; CAF, cancer-associated fibroblast; ECM, extracellular matrix; FAP, fibroblast activation protein; VDR ligands, Vitamin D receptor ligands.