Diacylglycerol kinase zeta (DGKζ)

Class

DGKζ inhibitor

Pathway

Intracellular T-cell checkpoint; DGKζ inhibition enhances T-cell priming/activation

Diacylglycerol kinase zeta (DGKζ) is an intracellular enzyme expressed in T cells that converts diacylglycerol (DAG), a lipid second messenger, into phosphatidic acid. When a T cell receptor engages its target, DAG accumulates and activates downstream signaling that drives T-cell activation, proliferation, and effector function. DGKζ acts as a brake on this process by depleting DAG, functioning as an internal, or 'intracellular,' checkpoint that limits how strongly and how long a T cell responds. Inhibiting DGKζ removes this brake, allowing DAG to persist and amplifying T-cell receptor signaling, which can strengthen T-cell priming and activation. This rationale is of particular interest in oncology, where tumors often exploit regulatory mechanisms, including intracellular checkpoints like DGKζ, to blunt anti-tumor immune responses. By enhancing T-cell activity from within the cell rather than blocking an inhibitory receptor on its surface, DGKζ inhibition represents a mechanistically distinct approach to immune modulation relative to surface checkpoint blockade. More broadly, this class of target is relevant wherever insufficient T-cell activation contributes to disease, including certain cancers and possibly chronic infections.