Immunotherapy for tuberculosis: current landscape, mechanistic insights, and translational perspectives

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from a single infectious agent worldwide, with 10.7 million new cases and 1.23 million deaths reported globally in 2024. Although conventional chemotherapy cures most drug-susceptible TB, the rising burden of multidrug-resistant TB (MDR-TB), prolonged treatment regimens, and suboptimal patient adherence continue to undermine control efforts. Against this background, immunotherapeutic approaches have gained renewed interest as rational complements to chemotherapy, building on decades of mechanistic work that has mapped host-pathogen interactions at unprecedented resolution. This review integrates recent advances across the immunotherapy landscape, including next-generation vaccines (M72/AS01E, MTBVAC, VPM1002, BNT164 mRNA candidates), host-directed therapies (HDTs) targeting autophagy, metabolic and inflammatory pathways, cytokine-based and antimicrobial peptide strategies, and adoptive cell therapies. We place particular emphasis on the dual, context-dependent roles of immune checkpoints such as PD-1/PD-L1 in TB, where checkpoint blockade can paradoxically trigger reactivation, and on the cellular heterogeneity revealed by single-cell and spatial transcriptomics of the granuloma. Key translational challenges-the absence of reliable correlates of protection, the demand for precision immunomodulation in comorbid populations (HIV, diabetes), and chronic underfunding of TB research-are discussed alongside emerging opportunities offered by mRNA platforms, repurposed drugs, and multi-omics-guided patient stratification. Collectively, immunotherapy is evolving from an adjunctive concept into a strategic pillar of TB control, with the potential to shorten treatment, prevent relapse, and address drug-resistant disease.