Lactic acid modulates immune cell function, particularly in macrophages, by influencing epigenetic regulation. This study shows that lactic acid acts as a primary fuel source for the TCA cycle, promoting histone H3K27 acetylation, which leads to the expression of immunosuppressive genes like Nr4a1. This process represses macrophage pro-inflammatory responses and induces a form of long-term immunosuppression called "trained immunosuppression." Lactic acid exposure reduces pro-inflammatory gene expression and chromatin accessibility to inflammatory gene loci, while increasing chromatin accessibility to genes involved in cell cycle and gene regulation. Lactic acid also enhances citrate production in the TCA cycle, which is essential for acetyl-CoA generation and histone H3K27 acetylation. This epigenetic modification represses pro-inflammatory gene expression by altering enhancer activity. The study further shows that lactic acid induces the expression of Nr4a1, a transcription factor that plays a key role in immunosuppression. Lactic acid-induced immunosuppression is independent of M2 macrophage polarization and is mediated through epigenetic reprogramming. The findings suggest that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment. These results have implications for the treatment of inflammatory diseases, as targeting lactic acid-induced trained immunosuppression in macrophages could be beneficial for managing inflammation.Lactic acid modulates immune cell function, particularly in macrophages, by influencing epigenetic regulation. This study shows that lactic acid acts as a primary fuel source for the TCA cycle, promoting histone H3K27 acetylation, which leads to the expression of immunosuppressive genes like Nr4a1. This process represses macrophage pro-inflammatory responses and induces a form of long-term immunosuppression called "trained immunosuppression." Lactic acid exposure reduces pro-inflammatory gene expression and chromatin accessibility to inflammatory gene loci, while increasing chromatin accessibility to genes involved in cell cycle and gene regulation. Lactic acid also enhances citrate production in the TCA cycle, which is essential for acetyl-CoA generation and histone H3K27 acetylation. This epigenetic modification represses pro-inflammatory gene expression by altering enhancer activity. The study further shows that lactic acid induces the expression of Nr4a1, a transcription factor that plays a key role in immunosuppression. Lactic acid-induced immunosuppression is independent of M2 macrophage polarization and is mediated through epigenetic reprogramming. The findings suggest that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment. These results have implications for the treatment of inflammatory diseases, as targeting lactic acid-induced trained immunosuppression in macrophages could be beneficial for managing inflammation.