Macrophage-state heterogeneity as the basis for host-directed therapy in tuberculosis

Tuberculosis (TB) persists partly because Mycobacterium tuberculosis (Mtb) occupies macrophages that differ in antimicrobial activity, nutrient use, inflammatory output, and drug exposure. This review examines how macrophage origin and lesion position influence phagosome maturation, responses to membrane damage, xenophagy, cytosolic sensing, regulated cell death, metabolism, and treatment response. Mtb can be taken up without lysosomal destruction, recognized by autophagy without completing lysosomal degradation, exposed to inflammatory signaling without effective killing, or retained in lesion regions with inadequate antibiotic concentrations. Evidence from single-cell studies, spatial analyses, experimental infection models, and clinical host-directed therapy studies supports evaluation of macrophage states rather than a fixed binary classification. Therapeutic candidates should be judged by linked host and bacterial outcomes, including completion of phagolysosomal or xenophagic degradation, viable bacterial burden, bacterial stress, preservation of macrophage and tissue function, lesion exposure, and compatibility with antimicrobial regimens. The evidence remains uneven: several mechanisms are well established, whereas many host-directed and nanomedicine approaches remain preclinical. Development should therefore use primary human macrophages, lesion-relevant models, lesion pharmacology, paired host-pathogen measurements, and separate microbiological, pathological, and functional endpoints. The aim is not broad immune stimulation but correction of defined macrophage and lesion states that permit persistence while preserving protective immunity.