Cancer-associated fibroblasts: The "Achilles' Heel" in thyroid tumor progression and therapy

Growing evidence indicates that the complex and heterogeneous tumor microenvironment (TME) beyond the tumor cells plays a pivotal role in cancer development and therapy. Notably, cancer-associated fibroblasts (CAFs)—a key stromal cell population within the TME—are closely associated with malignant tumor progression and therapeutic resistance and have progressively emerged as a research focus in oncology. As a major mesenchymal cell population in thyroid cancer (TC), CAFs exhibit high heterogeneity and dynamic plasticity. They secrete numerous cytokines and non-cytokine factors that abnormally remodel the extracellular matrix, directly influence the biological behavior of tumor cells, and concurrently modulate immune responses, consequently promoting therapeutic resistance. Given the unique and crucial role of CAFs in promoting TC progression, a thorough understanding of their intricate biology and the precise molecular mechanisms that regulate the malignant behavior of TC is essential for developing effective therapeutic strategies to improve outcomes for patients with TC. The present review provides an overview of the latest research advances on CAFs in TC, encompassing their origin, phenotype, and functional heterogeneity; the fundamental mechanisms by which CAFs promote TC progression and therapeutic resistance through bidirectional interactions with other TME components, including immune and tumor cells; and a systematic summary of therapeutic strategies targeting CAFs and their clinical translation outcomes. Furthermore, this review offers a concise perspective on future research directions in the field of CAFs. • Heterogeneity of Cancer-associated fibroblasts in thyroid cancer. • Cancer-associated fibroblasts are drivers of thyroid cancer progression. • Cancer-associated fibroblasts may constitute new therapeutic drug targets for thyroid cancer. • We provide new insights and perspectives on the pending issue of CAFs in thyroid cancer.