Exosomes Drive Thyroid Cancer by Rewiring Tumor Cell Metabolism

Thyroid cancer (TC) is the most common endocrine malignancy worldwide, with papillary thyroid carcinoma (PTC) comprising 80–85% of cases and generally favorable prognosis. However, anaplastic thyroid carcinoma (ATC) carries a median survival of only 3–6 months and a 5-year survival rate below 10%. Advanced and radioiodine-refractory cases remain poorly served by existing targeted therapies and immunotherapy, motivating the search for novel mechanistic insights.

This 2025 narrative review from Lanzhou University systematically synthesizes published evidence on how exosomes — nanoscale extracellular vesicles (30–150 nm) formed through endosomal multivesicular body fusion — mediate bidirectional metabolic crosstalk within the TC tumor microenvironment (TME). Unlike primary literature reporting original experiments, this work integrates molecular, cellular, and translational findings across the major TC subtypes.

Metabolic reprogramming in TC operates across three interconnected axes. In glucose metabolism, TC cells exploit the Warburg effect — preferring aerobic glycolysis even under normoxic conditions. Key enzymes HK2, PKM2, and PFK1 are overexpressed; HIF-1α drives GLUT1/GLUT3 upregulation and MCT4-mediated lactate export acidifies the TME, suppressing immune function and enabling invasion. In lipid metabolism, enzymes FASN, ACC, and ACLY are upregulated, fueling de novo fatty acid and cholesterol synthesis. Elevated 27-hydroxycholesterol, driven by reduced CYP7B1 and increased HMGCR/LDLR expression in PDTC and ATC, promotes malignant progression. In amino acid metabolism, ASCT2, GLS1, and LAT1 enhance glutamine uptake and catabolism, feeding the TCA cycle and supporting redox balance, especially in BRAF V600E-mutant PTC.

Exosomes amplify these metabolic programs through multiple mechanisms. Tumor cell-derived exosomes carrying LINC00460, miR-21, SNHG16, and metabolic enzymes reprogram cancer-associated fibroblasts (CAFs), macrophages, and endothelial cells toward pro-tumorigenic phenotypes. Conversely, CAF-derived and M2 macrophage-derived exosomes shuttle metabolic cargoes back to TC cells, reinforcing glycolytic and lipogenic dependency. Exosomes also mediate immune escape by polarizing macrophages to the M2 phenotype, suppressing CD8+ T cell activity, expanding Tregs, and altering NK cell function — all through metabolic signaling. Additionally, exosomal transfer of drug-resistance factors (e.g., multidrug resistance proteins, specific miRNAs) enables TC cells to survive chemotherapy and targeted therapy, including BRAF and RET inhibitors.

The review highlights the diagnostic potential of circulating exosomal miRNAs and proteins as liquid biopsy biomarkers for early TC detection, treatment monitoring, and prognostic stratification — particularly relevant for the 5–10% of DTC patients who develop radioiodine-refractory disease. Therapeutic strategies discussed include engineered exosomes as drug delivery vehicles, inhibitors of exosome biogenesis/release, and metabolic pathway blockade targeting glycolysis, fatty acid synthesis, or glutamine dependency in combination with immunotherapy.