Arginine and tryptophan metabolism are crucial for macrophage activation and immune responses during tuberculosis (TB). Arginine is metabolized by inducible nitric oxide synthase (iNOS) in M1 macrophages to produce nitric oxide (NO), which has antimicrobial properties, while arginase-1 (Arg1) in M2 macrophages converts arginine to ornithine, promoting tissue repair. Tryptophan is catabolized by indoleamine 2,3-dioxygenase 1 (IDO1) and IL4i1 to produce kynurenine and indole-3-pyruvic acid, which can suppress immune responses. These metabolic pathways are regulated by NAD+-dependent sirtuin proteins, particularly Sirt2 and Sirt5. Sirt2 regulates tryptophan catabolism via IL4i1, while Sirt5 influences arginine metabolism through the urea cycle. The balance between citrulline and ornithine production determines macrophage polarization and TB control. Arginine methylation and demethylation, mediated by Sirt2 and Sirt5, also impact macrophage function. Tryptophan catabolism contributes to NAD+ biosynthesis, which is essential for energy metabolism and immune responses. Targeting these metabolic pathways offers potential for host-directed therapies against TB. The interplay between arginine and tryptophan metabolism in macrophages is complex and critical for immune regulation and TB pathogenesis. Understanding these pathways may lead to new therapeutic strategies for TB treatment.Arginine and tryptophan metabolism are crucial for macrophage activation and immune responses during tuberculosis (TB). Arginine is metabolized by inducible nitric oxide synthase (iNOS) in M1 macrophages to produce nitric oxide (NO), which has antimicrobial properties, while arginase-1 (Arg1) in M2 macrophages converts arginine to ornithine, promoting tissue repair. Tryptophan is catabolized by indoleamine 2,3-dioxygenase 1 (IDO1) and IL4i1 to produce kynurenine and indole-3-pyruvic acid, which can suppress immune responses. These metabolic pathways are regulated by NAD+-dependent sirtuin proteins, particularly Sirt2 and Sirt5. Sirt2 regulates tryptophan catabolism via IL4i1, while Sirt5 influences arginine metabolism through the urea cycle. The balance between citrulline and ornithine production determines macrophage polarization and TB control. Arginine methylation and demethylation, mediated by Sirt2 and Sirt5, also impact macrophage function. Tryptophan catabolism contributes to NAD+ biosynthesis, which is essential for energy metabolism and immune responses. Targeting these metabolic pathways offers potential for host-directed therapies against TB. The interplay between arginine and tryptophan metabolism in macrophages is complex and critical for immune regulation and TB pathogenesis. Understanding these pathways may lead to new therapeutic strategies for TB treatment.