Lactic acid has emerged as a significant modulator of immune cell function, produced by gut microbiota and host metabolism. This study investigates how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory responses. The findings reveal that lactic acid serves as a primary fuel source for the tricarboxylic acid (TCA) cycle, promoting histone H3K27 acetylation. This modification allows the expression of immunosuppressive gene programs, including *Nr4a1*, which subsequently inhibits macrophage pro-inflammatory function. Additionally, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression, known as "trained immunosuppression." Pre-exposure to lactic acid induces lipopolysaccharide tolerance, suggesting that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment. The study highlights the importance of lactic acid in regulating macrophage function and its potential therapeutic applications in inflammatory diseases.Lactic acid has emerged as a significant modulator of immune cell function, produced by gut microbiota and host metabolism. This study investigates how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory responses. The findings reveal that lactic acid serves as a primary fuel source for the tricarboxylic acid (TCA) cycle, promoting histone H3K27 acetylation. This modification allows the expression of immunosuppressive gene programs, including *Nr4a1*, which subsequently inhibits macrophage pro-inflammatory function. Additionally, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression, known as "trained immunosuppression." Pre-exposure to lactic acid induces lipopolysaccharide tolerance, suggesting that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment. The study highlights the importance of lactic acid in regulating macrophage function and its potential therapeutic applications in inflammatory diseases.