Mechanisms of tumor-derived extracellular vesicle-mediated immunometabolic reprogramming and immunotherapeutic resistance.

backgroundTumor-derived extracellular vesicles (tEVs) are emerging as pivotal mediators of intercellular communication within the tumor microenvironment (TME). Beyond carrying oncogenic cargo, tEVs dynamically reprogram immune and metabolic networks that shape tumor progression and therapeutic response. MAIN BODY: In this review, we delineate how tEV-mediated immunometabolic rewiring orchestrates resistance to immunotherapy. We summarize recent findings that demonstrate how tEVs remodel glucose, lipid, and amino acid metabolism in immune cells, which in turn generates immunosuppressive microenvironments. These tEV-driven changes give rise to “metabolic checkpoints,” a newly recognized layer of immune regulation parallel to classical immune checkpoints. We further discuss how these metabolic alterations contribute to both primary and acquired immunotherapeutic resistance. Finally, we outline potential therapeutic strategies—including targeting tEV biogenesis, blocking tEV–immune interactions, and modulating metabolic checkpoints—and highlight how artificial intelligence (AI)-integrated tEV profiling and liquid biopsy may enable patient stratification and precision intervention.

conclusionsUnderstanding how tEV-mediated metabolic regulation shapes immune escape provides conceptual and translational opportunities. Integrating AI-driven analytics with tEV-based diagnostics may transform the prediction and reversal of immunotherapeutic resistance.