Small extracellular vesicles in tumor metabolism and immune escape: biomarkers and therapeutic opportunities.

Metabolic reprogramming is a key characteristic of cancer. It is increasingly seen as a process influenced by ongoing communication between cells in the tumor microenvironment (TME). Small extracellular vesicles (sEVs) are 30-100 nm membrane-bound particles that tumor cells release in large amounts. These vesicles play an important role in the exchange of metabolic information. Besides proteins and nucleic acids, sEVs carry bioactive metabolites, lipids, and metabolic enzymes that can change the energy and building processes in recipient cells. Although there is growing evidence that sEVs contribute to metabolic changes, a complete understanding of how their varied contents relate to coordinated changes in metabolism across tumor, immune, and stromal areas is still lacking. In this review, we summarize recent findings showing that tumor-derived sEVs function like "metabolic Trojan horses." They can trigger changes in glycolysis, accumulate lipids, and create dependencies on amino acids in recipient cells. This helps promote immune suppression, blood vessel growth, and resistance to treatment. We highlight the new idea of multi-metabolite sEV signaling as a factor in shaping the immunosuppressive environment of the TME. We also identify potential targets for intervention in sEV production, cargo loading, and cellular uptake, such as nSMase2, CD9/CD63-associated complexes, and macropinocytosis pathways. By combining insights from immunometabolism, cancer signaling, and the biology of extracellular vesicles, we propose that sEVs are not just biomarkers. They actively organize tumor metabolic systems and serve as valuable tools for precise immunology in cancer treatment.