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

Tumor-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. 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. Understanding 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. ∙ Tumor-derived extracellular vesicles (tEVs) play a critical role in orchestrating immune metabolic reprogramming within the tumor microenvironment (TME). ∙ We introduce the concept of “metabolic checkpoints”, offering novel mechanistic insights into tumor immune evasion and resistance to immunotherapy. ∙ Targeting metabolic checkpoints in combination with immune checkpoint inhibitors (ICIs) offers a promising strategy to overcome treatment resistance. ∙ Liquid biopsy platforms utilizing tEV-derived biomarkers, combined with artificial intelligence (AI), have transformative potential for real-time monitoring and personalized cancer immunotherapy. ∙ The integration of immunometabolism, extracellular vesicle biology, and computational analytics paves the way for a new frontier in precision oncology.