Histone H3K18 Lactylation Drives Immunosuppression by Upregulating CD38 in Myeloid-Derived Suppressor Cells in Lung Cancer

Abstract Histone lactylation is an epigenetic modification that connects lactate metabolism with protein function. Our study identified lactate enhances the protein lactylation level not only in Myeloid-derived suppressor cells (MDSCs) of tumor-bearing mice, but also in the tumor tissues of lung cancer patients. This modification led to upregulation of CD38 expression and enhanced the immunosuppressive function of MDSCs. Mechanistically, CD38 promoted immunosuppression by depleting NAD⁺, and treatment with CD38 inhibitor or siRNA-mediated knockdown of CD38 in MDSCs delayed tumor progression. H3K18la is enriched at CD38 promoter region, with p300, HDAC1-3, and BRD4 identified as key epigenetic regulators in this process. Our findings reveal the critical role of the lactate-CD38-NAD⁺ axis in regulating MDSC immunosuppressive function and establish histone lactylation as an epigenetic mechanism controlling CD38 expression.