Based on our findings, DOCK8 mutation disrupts BCR signaling and cytoskeletal remodeling, leading to impaired MZ and GC B cell development, and also induces metabolic reprogramming characterized by enhanced glycolysis and reduced PI3K-AKT-mTOR signaling, thereby affecting immune responses and offering new insights into the pathogenesis of DOCK8-related immunodeficiencies. Here, MTOR is linked to immunodeficiency disease.