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.