Immunotherapy for tuberculosis: emerging modalities, cross-disciplinary innovations, and roadmaps for drug-resistant disease.

RATIONALE: The emergence of multidrug-resistant tuberculosis (MDR-TB) and limitations of current antibiotic therapies highlight the urgent need for novel treatment strategies. While immunotherapy has revolutionized cancer treatment, its potential in TB remains underexplored, with existing reviews focusing narrowly on vaccines and phage therapy. A comprehensive synthesis of TB immunotherapy advancements is critical to guide clinical translation.

CONTENT: Tuberculosis (TB) has been recognized as one of the earliest diseases treated with immunotherapy. The BCG vaccine played a crucial role in controlling TB epidemics for a long period. However, progress in TB immunotherapy stagnated due to the attenuation of BCG strains and the long-standing neglect in TB immunology research. In recent years, advances in TB and immunology research, including novel immunological theories such as trained immunity, alongside breakthroughs in various immunotherapies for cancer treatment, have provided new perspectives for TB treatment. This review summarizes the immune response to TB, including roles of macrophages, T cells, and nonclassical immune cells. It evaluates progress in cell therapy, antibody therapy, microbial therapy, vaccines, and cytokine therapy. Clinical trials, mechanisms, and challenges (e.g., immune exhaustion, antigen heterogeneity) of TB immunotherapy are analyzed, drawing parallels with cancer immunotherapy.

CONCLUSIONS

Immunotherapy offers multifaceted strategies to overcome Mtb drug resistance and reduce side effects. Key directions include identifying novel antigens, optimizing immune checkpoint modulation, and combining therapies. Advances in single-cell sequencing and bioengineering will accelerate development, making immunotherapy a promising adjunct to conventional TB treatment.