Autophagy in thyroid cancer: Immune suppression and drug resistance

Thyroid cancer exhibits a broad spectrum of clinical behaviors, ranging from indolent differentiated tumors to highly aggressive, dedifferentiated malignancies that are refractory to radioactive iodine (RAI), targeted therapy, and immunotherapy. Autophagy, a highly conserved lysosome-mediated degradation pathway, has been identified as a crucial homeostatic mechanism with either tumor-suppressive or tumor-promoting effects depending on the regulatory context. Increasing evidence suggests that while basal autophagy may help attenuate genomic instability during early tumorigenic stages, advanced-stage tumors are more likely to utilize autophagic flux as a survival mechanism to maintain metabolic fitness, mitochondrial integrity, and resistance to therapeutic stress. This review integrates existing knowledge on the role of autophagy as a central hub amenable to drug targeting. It links MAPK-stimulated dedifferentiation and resistance to RAI with immune evasion and resistance to tyrosine kinase inhibitors and immune checkpoint blockade. Furthermore, we address the limitations of redifferentiation strategies and targeted therapies due to therapy-induced autophagy. We also discuss how autophagy modulates antitumor immunity within the tumor microenvironment, including its effects on antigen presentation, immune-cell polarization, and cytokine signaling. Emerging concepts, such as mitophagy sodium/iodide symporter (NIS) coupling, autophagy-exosome crosstalk, and compartment-specific autophagy requirements, are highlighted as understudied but therapeutically relevant areas. Additionally, we discuss the translational potential of next-generation lysosome-targeted agents, transcriptional regulators of the autophagy-lysosomal pathway, and selective autophagy-based degraders. Collectively, current evidence supports a genotype-, flux-, and timing-guided framework for modulating autophagy to overcome resistance and improve long-term disease control in advanced thyroid cancer.