Host-directed therapeutic targets in macrophages and their ligands against mycobacteria tuberculosis.

Although current combination regimens of antibiotics have significantly improved tuberculosis (TB) cure rates, substantial challenges persist in the global effort to end TB. These include poor patient compliance, the emergence of drug-resistant strains due to prolonged treatments, and the persistence of latent TB infections. Host-directed therapies (HDTs) have emerged as a promising complementary strategy, leveraging the modulation of host immune responses to combat Mycobacterium tuberculosis (Mtb). Unlike conventional antibiotics, HDTs can enhance therapeutic outcomes by boosting host defense mechanisms, reducing treatment duration and dosage, and minimizing the risk of resistance development. Notably, several HDTs have shown significant efficacy against multidrug-resistant (MDR) Mtb strains, while also mitigating excessive inflammation and lowering relapse rates-achievements that remain elusive with antibiotic regimens alone. This review provides a comprehensive overview of recent advancements in HDTs, focusing on druggable targets and the mechanisms by which these therapies restore or enhance immune functions disrupted by Mtb. By integrating insights into macrophage polarization, metabolic modulation, autophagy promotion, and cell death regulation, HDTs offer innovative and multifaceted approaches to TB treatment. Furthermore, the potential for HDTs to synergize with existing antibiotics underscores their relevance in overcoming current therapeutic limitations. This synthesis aims to inspire further research and development, with the ultimate goal of advancing HDTs as a transformative solution for TB management.