CCL20/CXCL5 Drives Crosstalk Between Anaplastic Thyroid Cancer Stem Cells and Tumor‐Associated Macrophages to Promote Tumor Progression

Abstract The dynamic interplay between tumor‐associated macrophages (TAMs) and anaplastic thyroid cancer (ATC) shapes the tumor microenvironment and facilitates ATC progression. However, the mechanisms of communication between TAMs and anaplastic thyroid cancer stem cells (ATCSCs) remain largely unelucidated. Integrative analyses of single‐cell RNA sequencing, cytokine/chemokine arrays, proteomics, and mRNA expression datasets are performed to reveal crosstalk between TAMs and ATCSCs and signaling pathways in ATCSCs. Subsequently, in vitro experiments are performed to validate the regulatory effects of key cytokines on ATCSC stemness. Last, xenogeneic orthotopic thyroid ATCSCs transplantation models are utilized to corroborate the regulatory effect of cytokines on stemness. CCL20 derived from THP‐1‐M2 activates the IRAK‐1/NF‐κB1/2 signaling pathway in ATCSCs, thereby positively regulating stemness characteristics and upregulating CXCL5 secretion. ATCSCs not only exhibit autocrine CXCL5 participation in the regulation of stemness but also demonstrate paracrine CXCL5 activity to recruit THP‐1‐Mφ and maintain the M2 phenotype. CCL20 and CXCL5 are involved in the crosstalk between TAMs and ATCSCs. The CCL20/CXCL5 axis plays a crucial role in the interaction between TAMs and ATCSCs, establishing a progressive tumor microenvironment.