Targeting alveolar macrophages in tuberculosis: Exploiting trained immunity for novel therapeutic approaches.

Tuberculosis (TB) is an airborne infectious disease caused by the Mycobacterium tuberculosis (Mtb) complex organism. Alveolar macrophages (AMs) play key roles in immune defense, antigen presentation, immune regulation, and immune secretion during Mtb infection. Notably, AMs exhibit context-dependent dual functions: protective and pathogenic. This duality is driven by the heterogeneous composition of AM subsets and their distinct immune profiles. On one hand, they fight against Mtb through a series of mechanisms to protect the host; on the other hand, certain AM subsets may provide a permissive niche that facilitates Mtb survival and persistence. Mtb possesses unique cell surface lipids and secreted protein effectors that enable it to evade the killing effects of innate immune cells and preferentially establish an ecological niche within AMs. AMs not only strengthen their antibacterial capabilities through mechanisms such as training immune memory, metabolic reprogramming, cytokine production, and autophagy, but also collaborate with other immune cells to jointly maintain immune balance within the body. Once this balance is disrupted, tuberculosis infection may run rampant. Furthermore, this article summarizes the potential role of different methods for inducing trained immune AMs in the treatment of tuberculosis, including existing bacille Calmette-Guérin (BCG) vaccination and emerging strategies such as lipopolysaccharide (LPS)-mediated Toll-like receptor 4 (TLR4) activation and Influenza A virus (IAV)-induced host trained immunity activation, providing new ideas for the treatment of tuberculosis.