Host-directed immunotherapy to enhance treatment of Mycobacterium tuberculosis infection

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the leading causes of morbidity and mortality worldwide, particularly in low- and middle-income countries. The extensive use of antibiotics has led to the emergence of multidrug-resistant and extensively drug-resistant MTB strains, intensifying the challenges associated with TB treatment. In this context, host-directed immunotherapy has emerged as a promising adjunct strategy that aims to modulate the host immune response rather than directly targeting the pathogen. By leveraging host-pathogen interactions, such approaches may enhance immune clearance, reduce treatment duration, and limit tissue damage. This review comprehensively summarizes current knowledge on host immune responses to MTB infection, mechanisms of immune defense, recent advances in host-targeted immunotherapeutic interventions and the challenges for TB treatment. A deeper understanding of these host-directed therapies is crucial for combating MTB infections and offers novel, resistance-independent treatment options to counteract resistance issues in TB management. Combining host-directed therapies with conventional antibiotics may improve treatment outcomes and reduce drug resistance, though further optimization in terms of delivery systems, efficacy, and safety remains necessary.