LCK is a non-receptor tyrosine kinase essential for T-cell development and immune function 1. It constitutively associates with the cytoplasmic portions of CD4 and CD8 receptors and initiates TCR-CD3 signaling by phosphorylating immunoreceptor tyrosine-based activation motifs (ITAMs) on TCR-γ chains and CD3 subunits 12. Upon TCR stimulation, LCK phosphorylates and activates ZAP70, recruiting downstream signaling cascades that culminate in lymphokine production 1. LCK activity is finely regulated through post-translational modifications; SIRT2-mediated deacetylation at lysine K228 governs LCK conformation and determines TCR signaling threshold 3. UBR2-induced K63-linked ubiquitination at lysine residues further modulates LCK activation downstream of TCR signaling 4. CD28 co-stimulation enhances LCK recruitment to TCR microclusters, increasing ZAP70 activation and lowering TCR activation thresholds 5. Beyond T-cell signaling, LCK promotes glioblastoma cell migration and stemness through Paxillin and Crk-II phosphorylation 6. Aberrant LCK activation drives ~40% of T-cell acute lymphoblastic leukemia (T-ALL), making LCK inhibition via dasatinib or ponatinib a promising therapeutic strategy 78. Dysregulated LCK signaling also underlies Immunodeficiency 22.