Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) limit the efficacy of adoptive T cell therapies, highlighting the need to overcome tumor-associated immunosuppression. Sphingosine-1-phosphate (S1P), is an abundant signaling lipid in the TME. Here, we show that inhibition of sphingosine kinase-2 (SphK2), the enzyme generating S1P in MDSCs, reduces the suppressive activity of monocytic MDSCs (M-MDSCs) while promoting their differentiation toward a mature, immunogenic phenotype characterized by enhanced antigen presentation. Pharmacological SphK2 inhibition enhances the response to anti–PD–1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC-mediated suppression and limiting tumor progression. Mechanistically, S1P directly binds acetyl-CoA carboxylase-1 (ACC1) to inhibit its activity, thereby rewiring fatty-acid metabolism. Lowering intracellular S1P restores ACC activity, promotes phosphatidylcholine synthesis, and reduces MDSC immunosuppression. These findings identify the SphK2–ACC–phospholipid axis as a metabolic checkpoint controlling the immunogenicity of MDSCs and a potential therapeutic target for enhancing cancer immunotherapy. Myeloid-derived suppressor cells limit anti-tumor immunity and checkpoint immunotherapy efficacy. The authors here find that SphK2-derived S1P binds and inhibits acetyl-CoA carboxylase, suppressing phosphatidylcholine biosynthesis, and SphK2 inhibition reprograms myeloid-derived suppressor cells, enhances T cell responses, and improves checkpoint therapy efficacy.
Chakraborty et al. (Tue,) studied this question.