Autophagy in <i>Mycobacterium tuberculosis</i> defense: unraveling complexities and reconciling contradictions

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge, exacerbated by prolonged treatment regimens, variable vaccine efficacy, and the emergence of drug-resistant strains. Beyond conventional pathogen-targeted antibiotics, increasing attention has focused on host-directed therapies (HDTs) that aim to enhance intrinsic immune mechanisms to improve disease control and treatment outcomes. Among these, autophagy, a conserved cellular process responsible for the degradation and recycling of damaged organelles, proteins, and intracellular pathogens, has emerged as a promising, yet complex, target in TB. Autophagy contributes to host defense by restricting intracellular M. tuberculosis survival, shaping innate and adaptive immune responses, and intersecting with antimicrobial effector pathways. However, the literature presents seemingly contradictory findings, with autophagy reported as both protective and insufficient, or even subverted, during infection. In the present Perspective, we critically examine these discrepancies and reconcile them by highlighting the influence of infection burden, disease stage, host cell type, and experimental context on autophagic outcomes. We further discuss how M. tuberculosis actively modulates autophagy to promote persistence and how the host counterbalances these strategies through interconnected immune pathways. Importantly, we position autophagy modulation within the broader framework of HDT for TB, critically evaluating pharmacological agents known to influence autophagic pathways, their potential therapeutic benefits, and their current limitations. We also address key translational challenges, including strain heterogeneity, cell-specific targeting, and drug delivery to infected macrophages. Finally, we outline future directions required to safely and effectively harness autophagy as an adjunctive strategy to shorten treatment duration and improve clinical outcomes in TB.