Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, poses a major global health challenge. The ability of the bacterium to manipulate the host immune system for survival, coupled with the increasing emergence of drug-resistant strains, is expected to escalate future health burdens. Additionally, patient noncompliance and prolonged therapy challenge traditional antibiotic treatments. Considering these challenges, host-directed therapies such as immunomodulatory therapy focus on enhancing host immunity rather than directly targeting the pathogen, which can be promising adjuncts to conventional tuberculosis treatment. This chapter explores various immunomodulatory approaches, including cytokine-based interventions, host-directed therapies, cell-based treatments, and immune checkpoint blockade strategies. Cytokines such as granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-32 have shown potential in stimulating immune responses and reducing bacterial burden. However, stability, cost, and specificity challenges limit their widespread application. In addition to these cytokine-based approaches, host-directed therapies leverage host pathways to combat infection, with autophagy inducers such as vitamin D3 and metabolic modulators such as metformin and statins demonstrating efficacy in promoting bacterial clearance. Advancements in cell-based therapies have shown promise in enhancing immune function and accelerating pathogen clearance, which includes utilizing mesenchymal stem cells, Vγ9Vδ2 T cells, and mucosal-associated invariant T cells. Additionally, targeting immune checkpoints such as programmed death-1 and its ligand can strengthen host defenses against Mycobacterium tuberculosis by reinvigorating exhausted T cells. Parallel to these therapeutic developments, novel TB vaccines are undergoing extensive evaluation. While the Bacillus Calmette-Guérin vaccine remains the only licensed TB vaccine, innovations in subunit, whole-cell, and mRNA-based vaccine platforms are progressing. Notable candidates such as M72:AS01E and MTBVAC demonstrate promise in enhancing disease prevention. Despite these advancements, challenges such as variable host immune responses, high production costs, and the need for large-scale clinical validation persist. Future research should prioritize clinical trials integrating these immunomodulatory strategies with standard TB regimens to assess their efficacy, safety, and real-world applicability. By shifting the treatment paradigm from pathogen elimination to host resilience, immunomodulatory therapy represents a crucial advancement in redefining TB treatment and control strategies.

Immunomodulators as Therapy for Mycobacteria

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发表日期：

2026年

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Falguni Agrawal,
Anand Kumar Maurya

摘要

Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, poses a major global health challenge. The ability of the bacterium to manipulate the host immune system for survival, coupled with the increasing emergence of drug-resistant strains, is expected to escalate future health burdens. Additionally, patient noncompliance and prolonged therapy challenge traditional antibiotic treatments. Considering these challenges, host-directed therapies such as immunomodulatory therapy focus on enhancing host immunity rather than directly targeting the pathogen, which can be promising adjuncts to conventional tuberculosis treatment. This chapter explores various immunomodulatory approaches, including cytokine-based interventions, host-directed therapies, cell-based treatments, and immune checkpoint blockade strategies. Cytokines such as granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-32 have shown potential in stimulating immune responses and reducing bacterial burden. However, stability, cost, and specificity challenges limit their widespread application. In addition to these cytokine-based approaches, host-directed therapies leverage host pathways to combat infection, with autophagy inducers such as vitamin D3 and metabolic modulators such as metformin and statins demonstrating efficacy in promoting bacterial clearance. Advancements in cell-based therapies have shown promise in enhancing immune function and accelerating pathogen clearance, which includes utilizing mesenchymal stem cells, Vγ9Vδ2 T cells, and mucosal-associated invariant T cells. Additionally, targeting immune checkpoints such as programmed death-1 and its ligand can strengthen host defenses against Mycobacterium tuberculosis by reinvigorating exhausted T cells. Parallel to these therapeutic developments, novel TB vaccines are undergoing extensive evaluation. While the Bacillus Calmette-Guérin vaccine remains the only licensed TB vaccine, innovations in subunit, whole-cell, and mRNA-based vaccine platforms are progressing. Notable candidates such as M72:AS01E and MTBVAC demonstrate promise in enhancing disease prevention. Despite these advancements, challenges such as variable host immune responses, high production costs, and the need for large-scale clinical validation persist. Future research should prioritize clinical trials integrating these immunomodulatory strategies with standard TB regimens to assess their efficacy, safety, and real-world applicability. By shifting the treatment paradigm from pathogen elimination to host resilience, immunomodulatory therapy represents a crucial advancement in redefining TB treatment and control strategies.