Tuberculosis Immunotherapy Advances: Integrating Next-Gen Vaccines, HDTs, and Peptides to Combat Drug Resistance

Despite conventional chemotherapy, Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from a single infectious agent, with 10.7 million new cases and 1.23 million deaths reported globally in 2024. The rising burden of multidrug-resistant TB (MDR-TB), prolonged treatment regimens, and suboptimal patient adherence severely undermine control efforts. Immunotherapeutic approaches are gaining renewed interest as rational complements to chemotherapy, leveraging decades of mechanistic work on host-pathogen interactions to address these critical gaps in current treatment paradigms.

This review integrates recent advances across the tuberculosis (TB) immunotherapy landscape. It examines next-generation vaccines, including candidates like M72/AS01E, MTBVAC, VPM1002, and BNT164 mRNA platforms. The scope also covers host-directed therapies (HDTs) that target host autophagy, metabolic, and inflammatory pathways, as well as cytokine-based and antimicrobial peptide strategies. Furthermore, the review explores adoptive cell therapies and emphasizes the dual, context-dependent roles of immune checkpoints such as PD-1/PD-L1 in TB pathogenesis, alongside insights from single-cell and spatial transcriptomics of the granuloma.

The review highlights that immunotherapy is transitioning from an adjunctive concept to a strategic pillar in TB control, offering potential to shorten treatment, prevent relapse, and address drug-resistant disease. It details how next-generation vaccines and host-directed therapies targeting pathways like autophagy and inflammation are showing promise. The complex, dual roles of immune checkpoints, such as PD-1/PD-L1, are emphasized, where blockade can paradoxically trigger reactivation, underscoring the need for precision immunomodulation. Single-cell and spatial transcriptomics have revealed significant cellular heterogeneity within the granuloma, providing new targets for intervention. Emerging opportunities include mRNA platforms, repurposed drugs, and multi-omics-guided patient stratification. The global burden of 10.7 million new cases and 1.23 million deaths in 2024 underscores the urgency for these novel approaches. > 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.