Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling

Abstract

Metabolic reprogramming is one of the fundamental characteristics of thyroid cancer (TC), which meets its energy and biosynthetic demands through mitochondrial dysfunction, glycolysis activation, lipid metabolism imbalance, and glutamine dependency, thereby promoting metastasis and reshaping the immune microenvironment. Exosomes, as extracellular vesicles, play a crucial role in TC by delivering bioactive molecules such as proteins, lipids, and nucleic acids. In the tumor microenvironment (TME) of TC, exosomes secreted by both tumor and non-tumor cells interact with each other, driving metabolic reprogramming and forming a bidirectional regulatory network. This significantly alters the biological characteristics of TC cells, including proliferation, invasion, metastasis, angiogenesis, and the acquisition of drug resistance and immune tolerance, ultimately influencing the process of immune escape in TC. This review systematically summarizes how exosomes in the TME of TC promote tumor progression through metabolic reprogramming, providing new diagnostic and therapeutic strategies for patients with locally advanced, radioiodine-refractory TC.

Keywords: Exosomes; Immune escape; Metabolic reprogramming; Thyroid cancer; Tumor microenvironment.

Fig. 1

Metabolic reprogramming in TC. In the TME, TC cells reprogram their energy metabolism to gain an advantage. Compared with normal cells, TC cells take up more glucose, which is affected by the warburg effect and produces more lactate. In order to adapt to this process, the expression of transport receptors and metabolic enzymes involved in the glucose metabolism pathway is increased. In addition, the glycolytic pathway not only produces ATP, but also provides important metabolic intermediates for other biosynthetic pathways. Both fatty acid synthesis and fatty acid oxidation are upregulated to promote the progression of TC. The metabolic pathways of glutamine and serine are significantly upregulated, providing nitrogen and one-carbon units for the proliferation and invasion of TC cells. In the figure, the red arrows indicate an increase in the content or enhancement in the function of metabolic enzymes. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F1,6BP, fructose 1,6-bisphosphate; 3-PG, 3-phosphoglycerate; 2PG, 2-Phosphoglycerate; PEP, Phosphoenolpyruvate; αKG, α-ketoglutarate; TCA, tricarboxylic acid; FAO, fatty acid oxidation; VLDL, very low-density Lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; ACC2, Acetyl-CoA carboxylase 2; FASN, fatty acid synthase

Fig. 2

Mechanisms of exosomes biogenesis and internalization. Early endosomes (EE) are formed by the fusion of endocytosed vesicles, late endosomes are also known as MVBs, and exosomes are formed by the inward budding of multivesicular body membranes in the form of ILVs, which can be degraded by the lysosome or can also be released from the lumen into the extracellular compartment. Subsequently, exosomes can exert their biological activity through endocytosis, fusion with target cell membranes to release their contents, and direct interaction with cell surface receptors. Exosomes are composed of DNA, RNA, lipids, proteins, MHC receptors, transmembrane tetraspanins (CD9, CD63, CD81), integrins, programmed death-ligand 1 (PD-L1), flotillin, ALG-2 interacting protein X (ALIX), heat shock proteins (HSP70s), tumor susceptibility gene 101 (TSG101), Ras-related protein Rab27a (Rab27a), Heat shock cognate 10 (HSC10), and epidermal growth factor receptor (EGFR)

Fig. 3

Exosome-mediated metabolic reprogramming during progression of TC. Exosomes participate in tumor proliferation, angiogenesis, drug resistance, and immune suppression through metabolic reprogramming. By inducing glycolysis, exosomes accelerate the formation of pre-metastatic niches in TC and enhance the growth rate of TC. They can also activate angiogenic signaling pathways, induce glycolysis, and increase the viability of vascular endothelial cells, thereby meeting the nutrient demands of tumor cells. Exosomes reprogram the metabolic pathways of cancer cells, inducing drug resistance by accelerating drug efflux, altering the pH of the TME, upregulating anti-apoptotic factors, causing epigenetic changes, and promoting DNA repair. Exosomes released by tumor cells can lead to the formation of an immune suppression network by regulating metabolic reprogramming, enabling tumor cells to evade detection by the immune system. —|: Decreased expression/activity. ↑: Increased expression/activity. →: Direction of reaction or effect

Fig. 4

Exosome-Mediated Metabolic Reprogramming in TME. Exosomes circulating within the TME are crucial mediators of immune regulation and the modulation of tumor biological behaviors. In the TME of TC, exosomes derived from tumor cells or immune cells alter the metabolic processes of target cells, thereby influencing their biological properties. This includes modulating the function of CAFs, the immune response of lymphocytes, the M2 polarization of macrophages, the antigen-capturing activity of DCs, and the tumorigenic capacity of CSCs. Ultimately, by affecting the activity of immune-killing cells and promoting the activation of immunosuppressive cells, exosomes mediate the growth, invasion, and metastatic potential of tumor cells. ↓: Decreased expression/activity. ↑: Increased expression/activity. →: Direction of reaction or effect