FOXP Transcription Factors in Thyroid Cancer: From Molecular Expression to Clinical Significance

Thyroid cancer (TC) is the most common endocrine malignancy, with a steadily rising global incidence. Despite most cases having a favorable prognosis, a subset of patients develops aggressive, recurrent, or radioiodine-refractory disease, demonstrating the need for improved molecular biomarkers and targeted therapies. The Forkhead box P (FOXP) transcription factors (FOXP1-FOXP4) have appeared as important regulators of tumor biology, yet their roles in thyroid cancer remain incompletely defined. This review summarizes current bioinformatic, experimental, and clinical evidence regarding FOXP expression patterns, molecular mechanisms, and clinical relevance in TC. FOXP3 and FOXP4 are mainly associated with aggressive clinicopathological features, including extrathyroidal invasion, lymph node metastasis, and distant metastases, and may serve as markers of poor prognosis. The most explored FOXP3 contributes to immune evasion and radioiodine resistance by suppressing sodium iodide symporter expression and regulating tumor-associated immune responses. FOXP4 promotes tumor progression by activating key oncogenic signaling pathways and regulating non-coding RNAs. In contrast, evidence indicates that FOXP2 primarily acts as a tumor suppressor in TC by inhibiting cell proliferation and promoting apoptosis, although it may show context-dependent functions. FOXP1, though less well studied, is also suggested to have tumor-suppressive effects in some studies, and demands additional investigation in TC. Collectively, current evidence suggests that FOXP family members may represent promising diagnostic, prognostic, and therapeutic biomarkers in thyroid cancer, although further validation in large clinical cohorts and mechanistic studies is still required.