Phosphatidylcholine regulation via sphingosine kinase 2 inhibition drives immunogenic reprogramming of myeloid-derived suppressor cells 3701

Abstract Description Immunosuppressive myeloid populations, like myeloid-derived suppressor cells (MDSCs), within the tumor microenvironment (TME), hinder cancer immunotherapy. Targeting this suppression is vital to enhance anti-tumor T cell function in the TME. Our research shows that inhibiting SphK2-mediated S1P generation in MDSCs reshapes the TME, promoting tumor control. In preclinical checkpoint-resistant breast, bladder, and melanoma cancer models, SphK2 inhibition sensitizes tumors to anti-PD1 therapy, reducing tumor growth by alleviating MDSC suppression. Mechanistically, the MS-based proteomics analysis revealed that S1P interacts with Acetyl CoA carboxylase isoforms (ACC1 and ACC2), key enzymes in fatty acid metabolism. Enhancing ACC1/2 activity reprograms MDSC metabolism by increasing glycolysis through elevated Pyruvate Kinase M2 activity while reducing fatty acid oxidation. This metabolic shift promotes an immunogenic MDSC phenotype, enhancing antigen presentation to T cells. Moreover, lipidomic analysis showed that altered ACC1/2 activity increases fatty acid synthesis, particularly phosphatidylcholine (PC). Notably, PC supplementation alleviates ER stress in tumor-associated MDSCs, a key driver of their suppressive function. These findings establish S1P as a critical immunoregulatory mediator and PC as an immunostimulatory molecule, highlighting the SphK2/ACC/phospholipid axis as a promising target to counteract immunosuppression and enhance the efficacy of cancer immunotherapy. Funding Sources Department of Surgery, MUSC, Swim Across America foundation (SAA) NCI R01 CA250458, R01 CA236379 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)