Harnessing lipid metabolism through diacylglycerol kinases: implications for immune modulation and cancer therapy

Diacylglycerol kinases (DGKs) are key enzymes that integrate lipid metabolism with multiple signaling pathways. DGKs regulate the conversion of diacylglycerol (DAG) into phosphatidic acid (PA), two essential bioactive lipids that promote the activation of distinctive proteins controlling cell growth, proliferation and differentiation. The variety of DGK isoforms enables them to perform specialized functions in different tissues, and dysregulation of DGK activity and expression contributes to diverse pathological conditions. DGKs exert potent inhibitory functions in T cells and are aberrantly expressed in a wide range of cancer types, which make DGKs attractive therapeutic targets for cancer immunotherapy. In recent years, the development of novel and highly isoform-specific inhibitors has opened exciting opportunities to further explore the fundamental functions of lipid metabolism in the maintenance of immune cell homeostasis and in the progression of several diseases. Besides T cells, DGKs play important roles in regulating inflammatory processes across distinct immune populations. The therapeutic potential of these drugs has been translated in several ongoing clinical trials. Therefore, it is crucial to delineate DGK-controlled signaling hubs to better understand their impact on immune signatures. In this work, we aimed to recapitulate the effects of modulating DAG/PA balance on immune cells that are relevant in the tumor microenvironment. By dissecting how DGK-mediated lipid signaling shapes immune cell behavior in the tumor microenvironment, we seek to provide mechanistic insights that may guide the rational use of drugs targeting DGKs to improve antitumor immunity.