Sodium Iodide I-131

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.

The dynamic characteristics of gut microbiome and metabolome during radiopharmaceutical therapy and their correlation with treatment response have not been well clarified. Herein, we conducted a prospective longitudinal study on papillary thyroid carcinoma patients receiving initial radioactive iodine (RAI) treatment. Three fecal samples from each patient were sequentially collected at the day before (Day0), 3 days upon (Day3), and 30 days upon (Day30) receiving RAI (totally 75 samples) for 16S rRNA amplicon sequencing and metabolome profiling. The results revealed transient fluctuations of gut microbiota and metabolites during RAI treatment, as shown by probiotic Blautia and anti-inflammatory and antioxidant metabolites first decreased on Day3 and then increased on Day30, while the opposite trends of opportunistic pathogens Streptococcus were observed. Meanwhile, correlation analysis showed a complex interplay between the temporal alterations of Blautia and the anti-inflammatory and antioxidant metabolites. Furthermore, the variability of intestinal flora and metabolites at multiple time points corresponded to the response to RAI treatment. In conclusion, our findings indicated that internal irradiation could lead to transient fluctuations of gut microbiota and metabolites, suggesting that probiotics might be beneficial for patients receiving RAI. Additionally, we provided a new perspective to screen for noninvasive biomarkers corresponding to the response to RAI treatment.

This study provides the first longitudinal profiling demonstrating that radioactive iodine (RAI) therapy induces transient yet dynamic fluctuations in both the gut microbiome and metabolome. Key beneficial bacteria and anti-inflammatory metabolites were significantly reduced immediately after treatment, followed by a recovery trend. Moreover, patients with different treatment responses showed diverse microbial and metabolic profiles. These findings highlight the potential for probiotic based interventions to maintain gut ecological homeostasis and suggest novel non invasive microbial biomarkers for predicting RAI efficacy. This study is registered with ClinicalTrials.gov as ChiCTR2100053810 .