Gut microbiome signatures of survival and immunotherapy response in advanced thyroid cancer

Introduction: Despite multimodal therapies, including surgery, radiation, and systemic treatments, advanced thyroid cancers such as anaplastic thyroid cancer (ATC) and medullary thyroid cancer (MTC) remain therapeutically challenging, with ATC continuing to carry a historic median survival of only 6 months, while MTC often being burdened with recurrences and distant metastases. Identifying predictive biomarkers for treatment response is crucial for improving outcomes. While gut microbiota have been shown to influence treatment efficacy in melanoma and colorectal cancer, its role in thyroid cancer has yet to be explored. This study investigates the gut microbiome in patients with ATC or MTC to identify microbial features associated with treatment response. Methods: Between April 2019 and September 2025, stool samples were collected from patients with ATC or MTC using a temperature-controlled at-home kit. Demographic, molecular, and treatment data were also collected. Overall survival was measured from cancer diagnosis to death, with censoring at last follow-up. Metagenomic sequencing data was processed using MetaPhlAn4. Diversity and taxonomic analyses were performed in R with phyloseq and MaAsLin2. Results: Analysis of stool microbiomes from 27 ATC and 24 MTC patients revealed no significant differences in major diversity metrics (alpha or beta diversity) across patient groups. However, compositional differences emerged when comparing survival outcomes. In ATC patients, long-term survivors (>1 year) exhibited an enrichment in short-chain fatty acid (SCFA)-producing bacteria, including Blautia obeum, Roseburia faecis, Fusicatenibacter saccharivorans, Eubacterium siraeum, and Coprococcus comes. Bacteria involved in polyphenol metabolism, such as Gordonibacter urolithinfaciens and Adlercreutzia equolifaciens, were also more abundant in patients with prolonged survival. In contrast, ATC patients with a survival of ≤1 year showed enrichment in Clostridium symbiosum, a pathobiont, and Collinsella aerofaciens, which is associated with systemic inflammation. Notably, in a subgroup of 21 ATC patients receiving immunotherapy, responders had a distinct microbiome signature enriched with Eubacterium ramulus, Faecalibacterium species, and Anaerotruncus massiliensis, all three being SCFA producers. In contrast, certain taxa traditionally associated with gut health, such as Christensenella minuta and Anaerostipes hadrus, were enriched in patients with ≤1 year survival, suggesting context-dependent roles in cancer progression and therapy. Interestingly, MTC patients with favorable outcomes, measured as long-term stable disease, also had gut microbiomes enriched with SCFA-producing bacteria, including Roseburia intestinalis, Faecalibacterium species, and Gemmiger formicilis. Conclusions: A microbiome enriched in SCFA-producing bacteria and polyphenol-metabolizing species is associated with improved survival and potentially favorable responses to immunotherapy. These findings place gut microbial taxa as candidate biomarkers of prognosis and immunotherapy response in advanced thyroid cancer and support prospective validation and mechanistic studies to define their potential as therapeutic targets or tools for microbiome-informed treatment stratification.