The Kynurenine Pathway in Tuberculosis: Focus on Immunometabolic Regulation, Compartment-Specific Biology, and...

Tuberculosis (TB) remains a global health problem, and attention is focused on host immunometabolic pathways influencing antimicrobial immunity, tissue injury, and treatment response. This comprehensive review integrates evidence on the kynurenine pathway (KP) of tryptophan (TRP) metabolism in TB and evaluates its potential as a host-directed therapeutic target. Evidence from human cohorts, in vitro systems, animal models, and non-human primates indicates that Mycobacterium tuberculosis activates the KP across myeloid, antigen-presenting, non-hematopoietic lung, granulomatous, pleural, and central nervous system compartments. KP activation is shaped by interferon-γ signaling, mycobacterial burden, infection duration, strain virulence, and host regulatory mechanisms. Increased indoleamine 2,3-dioxygenase-related (IDO) activity, TRP depletion, kynurenine accumulation, and kynurenine-aryl hydrocarbon receptor (AhR) signaling are associated with impaired T-cell proliferation and recruitment, suppressive myeloid phenotypes, and spatially restricted immunoregulatory niches within granulomas. Accumulated data indicate context-dependent protective effects of the KP manipulations, through restriction of excessive inflammation. Furthermore, the KP-related changes may have biomarker value. Integrated assessment of enzyme expression, kynurenine-to-tryptophan ratio (K/T ratio), downstream metabolites, and signaling pathways will be essential for translational studies. Future studies should therefore evaluate KP activity using integrated readouts, including IDO expression, metabolites and their ratios, and KYN-AhR signaling, and should determine whether context-specific pathway modulation can safely improve outcomes when combined with conventional anti-TB therapy.