Autophagy in thyroid cancer: stage-dependent switch, mutation-specific regulation, and therapeutic targeting

Autophagy plays context-dependent roles in thyroid cancer, but whether its dual nature represents a reversible balance or an irreversible stage-dependent switch has remained unclear. This review synthesizes evidence across papillary, follicular, medullary, and anaplastic thyroid carcinoma subtypes and reveals that the transition from tumor-suppressive to tumor-promoting autophagy is unidirectional and driven by disease progression, not a simultaneous equilibrium. The major driver mutations BRAF V600E, RAS, and RET regulate autophagy through distinct mechanisms, demanding subtype-specific therapeutic strategies rather than a uniform approach. Importantly, autophagy is an adaptive resistance mechanism rather than a primary driver, as no thyroid cancer is driven by mutations in autophagy genes. Consequently, autophagy inhibitors will not work as monotherapy but may sensitize tumors to standard treatments that create therapeutic stress. Current clinical translation remains stalled by poor inhibitor specificity, lack of validated biomarkers, and unknown treatment timing. We conclude that the field should move from descriptive studies to biomarker-enriched, hypothesis-driven trials, prioritizing anaplastic thyroid carcinoma for hydroxychloroquine-TKI combinations while standardizing assays for p62 and LC3B to enable patient selection.