Sphingosine Kinase-2 Inhibition Increases Acetyl-CoA Carboxylase Activity and Phosphatidylcholine Levels to Program Immunogenicity in Myeloid-Derived Suppressor Cells [ATAC-seq]

Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are a major barrier to adoptive T cell therapy, underscoring the need to enhance T cell efficacy by overcoming immunosuppression. Here, we investigated how sphingosine-1-phosphate (S1P), an abundant signaling lipid in the TME, regulates the programming and function of MDSCs. We show that inhibition of sphingosine kinase-2 (SphK2), which generates S1P in MDSCs, reduces their suppressive activity and enhances antigen presentation. Pharmacological inhibition of SphK2 improved the response to anti-PD1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSCmediated suppression, thereby limiting tumor progression. Mechanistically, S1P directly interacts with Acetyl-CoA Carboxylase 1 (ACC1) to inhibit its activity, altering fatty acid and glycolytic pathways. Lowering intracellular S1P restores ACC activity and promotes phosphatidylcholine synthesis, reducing the immunosuppressive phenotype of MDSCs. These findings highlight the SphK2/ACC/phospholipid axis as a promising therapeutic target in cancer immunotherapy.