LCK at the crossroad of immunodeficiency and autoimmunity: Mechanisms and therapeutic opportunities.

The lymphocyte-specific protein tyrosine kinase (LCK) is the principal initiator of T cell receptor (TCR) signaling and a critical regulator of T-cell development, activation, and immune tolerance. Its critical expression in T cells positions LCK as both a molecular gatekeeper of adaptive immunity and an attractive therapeutic target. Loss-of-function mutations in LCK result in combined immunodeficiency with profound defects in T-cell differentiation and signaling, whereas hypomorphic variants with residual activity can promote immune dysregulation and autoimmunity. Conversely, aberrant LCK activation is associated with autoimmunity and chronic inflammation, including type 1 diabetes, psoriasis, rheumatoid arthritis, asthma, multiple sclerosis, and graft-versus-host disease. Here, we review the structural and regulatory mechanisms of LCK, its dysfunction in immunodeficiency and autoimmunity, and the current landscape of therapeutic strategies. While first-generation inhibitors targeting the ATP-binding site have shown efficacy in preclinical models, their lack of selectivity highlights the need for innovative approaches directed at non-catalytic domains of LCK. By linking mechanistic understanding with clinical relevance, we position LCK as a precision regulatory node with the potential to transform therapeutic strategies for T cell-driven immune disorders.