Immune activation and regulation mediated by immune cell-derived EVs (iEVs).

Abstract

Extracellular vesicles (EVs), secreted by all cellular organisms, are pivotal mediators of intercellular communication. By transporting biologically active cargos such as proteins, lipids, and nucleic acids, EVs facilitate transfer of molecular signals, effectively reflecting the characteristics of their parent cells. Immune cellderived EVs (iEVs) play a crucial role in the activation and regulation of both adaptive and innate immune responses. In the context of immune activation, iEVs drive immune cell development and activation, as well as enhance antigen presentation through both direct and cross-dressing mechanisms. Furthermore, iEVs act as signaling entities within immunological synapses, significantly amplifying immune response efficiency. In immune regulation, iEVs modulate the expression of immune checkpoint (IC) molecules and sustain immune homeostasis by transporting immunosuppressive cytokines and microRNAs, thereby mitigating excessive immune reactions. Nevertheless, the mechanistic underpinnings of iEV-mediated immune cell activation, antigen presentation, and immunoregulation remain inadequately explored. This review provides a comprehensive overview of the functions of iEVs from diverse immune cell origins and underlying mechanisms. It also examines cutting-edge engineering strategies targeting iEVs and their parent cells, while discussing their promising applications in oncology and immune-related diseases. These insights lay the foundation for the rational development of next-generation immunotherapies. While promising, the clinical translation of iEVs is hindered by low yield, high batch-to-batch variability, and insufficient targeting efficiency. The final section discusses key challenges and potential solutions.