DOCK2 is a guanine nucleotide exchange factor specifically expressed in hematopoietic cells that plays critical roles in immune cell function and cytoskeletal reorganization 1. DOCK2 activates RAC1 and RAC2 GTPases, facilitating actin cytoskeleton rearrangement required for lymphocyte migration in response to chemokines 12. The protein is essential for proper immune cell activation and migration, with defects leading to impaired neutrophil cytoskeletal rearrangement and reactive oxygen species production 2. DOCK2 deficiency causes severe combined immunodeficiency, with patients presenting early-onset viral infections and Omenn syndrome due to complete loss of DOCK2 protein expression 2. Recent studies demonstrate DOCK2's broader clinical significance: reduced expression is associated with CD8+ T-cell exhaustion in hepatocellular carcinoma, where cholesterol sulfate suppresses DOCK2 enzymatic activity 3. Additionally, DOCK2 variants increase susceptibility to severe COVID-19, particularly in younger patients, with decreased expression correlating with impaired macrophage recruitment and dysregulated interferon responses 4. The TCR-SUB1-DOCK2 signaling axis also promotes autoimmunity by driving pathogenic CD4+ T cell tissue infiltration through enhanced cell motility 5. These findings establish DOCK2 as a crucial regulator of immune cell function with significant implications for immunodeficiency, cancer immunotherapy, and autoimmune diseases.