CD4 ⁺ Th Cell‐Derived Extracellular Vesicles Orchestrate CD8 ⁺ T Cells and Eosinophils to Enhance Anti‐Tumor Immunity

ABSTRACT CD4 ⁺ T cells play a pivotal role in anti‐tumor immunity by assisting CD8 ⁺ T cells in eliminating MHC I ⁺ tumor cells and promoting immune responses against MHC‐deficient tumors through myeloid‐cell recruitment. Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular immune communication; however, how CD4 ⁺ T helper (Th)‐derived EVs modulate tumor immune cells, including CD8 ⁺ T cells and eosinophils, to orchestrate anti‐tumor responses remains poorly understood. Here, we show that immune checkpoint molecules, including PD‐1 and TIM‐3, and the cytokine IL‐5 are enriched on CD4 ⁺ Th cell microvilli and EVs. Activated CD4 ⁺ Th cells released both exosomes and ectosomes, which cooperatively suppressed tumor progression through two complementary mechanisms. First, CD4 ⁺ Th‐derived exosomes and ectosomes displayed immune checkpoint receptors such as PD‐1 and TIM‐3 on their surface, thereby intercepting tumor‐derived inhibitory signals, reversing T cell exhaustion, and enhancing cytotoxic T cell activity. Second, CD4 ⁺ Th‐derived EVs carried IL‐5 and other effector molecules that promoted JAK–STAT signaling, eosinophil recruitment to tumor sites, and eosinophil‐mediated tumor cell killing through degranulation. Moreover, CD4 ⁺ Th‐derived EVs remodeled the tumor microenvironment by enhancing CD8 ⁺ T cell and eosinophil infiltration and activation, suggesting their potential role in immune regulation and cancer therapy.