Sphingosine Kinase-2 Inhibition Increases Acetyl-CoA Carboxylase Activity and Phosphatidylcholine Levels to Program Immunogenicity in Myeloid-Derived Suppressor Cells
Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are a major barrier toadoptive T cell therapy, underscoring the need to enhance T cell efficacy by overcomingimmunosuppression. Here, we investigated how sphingosine-1-phosphate (S1P), an abundant signalinglipid in the TME, regulates the programming and function of MDSCs. We show that inhibition of sphingosinekinase-2 (SphK2), which generates S1P in MDSCs, reduces their suppressive activity and enhancesantigen presentation. Pharmacological inhibition of SphK2 improved the response to anti-PD1 therapy inpreclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC-mediated suppression, thereby limiting tumor progression. Mechanistically, S1P directly interacts withAcetyl-CoA Carboxylase 1 (ACC1) to inhibit its activity, altering fatty acid and glycolytic pathways. Loweringintracellular S1P restores ACC activity and promotes phosphatidylcholine synthesis, reducing theimmunosuppressive phenotype of MDSCs. These findings highlight the SphK2/ACC/phospholipid axis asa promising therapeutic target in cancer immunotherapy.