ERα–PADI4–CXCL8 Axis Drives MDSC‐Mediated Immune Evasion in Anaplastic Thyroid Carcinoma

ABSTRACT Anaplastic thyroid carcinoma (ATC) is a highly lethal malignancy with a median survival of merely 4–6 months and no effective systemic therapies. Although ATC predominantly arises in elderly postmenopausal women with negligible circulating 17β‐estradiol (E2), we observed that estrogen receptor alpha (ERα) is constitutively phosphorylated at serine 118 (S118) in ATC tissues, independently of its canonical ligand. Here, we identify peptidyl arginine deiminase 4 (PADI4) as a direct transcriptional target of ligand‐independently activated ERα, driven by EGF/MAPK signaling. PADI4 is overexpressed in ATC along a dedifferentiation gradient, and its high expression defines an immune‐excluded tumor microenvironment characterized by dense CD33 + myeloid‐derived suppressor cell (MDSC) infiltration and CD8 + T cell exclusion, portending poor prognosis. Mechanistically, PADI4 citrullinates histone H3 at the CXCL8 promoter, opening chromatin and driving CXCL8 secretion, which recruits MDSCs through CXCR2. Pharmacological inhibition of PADI4 with GSK484 triggers compensatory CXCL1 upregulation, sustaining residual MDSC chemotaxis through CXCR1/2. Combined blockade of PADI4 (GSK484) and CXCR1/2 (SX‐682) synergistically suppresses tumor growth, eliminates pulmonary metastasis, and achieves 80% long‐term survival in an orthotopic ATC model, without appreciable systemic toxicity. These findings establish the ERα–PADI4–CXCL8–MDSC signaling axis as a central driver of immune evasion in ATC and provide a preclinical rationale for dual‐targeted epigenetic‐immunotherapy.