Immune activation and response dynamics of human <scp>iPSC</scp> ‐derived macrophages in tuberculosis infection models

Abstract Objectives Tuberculosis (TB) remains a global health challenge, with current antibiotic therapies being limited by long treatments, side effects and multidrug‐resistant mycobacterial strains. In addition, Mycobacterium tuberculosis ( Mtb ), the main causative agent of TB, employs evasion mechanisms particularly within alveolar macrophages being the primary host cells. Conventional therapies fail to modulate macrophage function or effectively target host immunity, which is crucial in TB pathogenesis. Emerging evidence points to induced pluripotent stem cell‐derived macrophages (iMacs) with enhanced bactericidal activity as a promising cell‐based approach for TB treatment. Therefore, this study aimed to compare iMacs with blood monocyte‐derived macrophages (MDMs) in response to Bacillus Calmette–Guérin (BCG), the live attenuated TB vaccine and heat‐killed Mtb (HKMT). Methods iMacs and MDMs were challenged with BCG and HKMT to assess their functional responses. Key parameters evaluated included cell migration, phagocytosis kinetics, levels of autophagy‐ and apoptosis‐related proteins, and cytokine production profiles following infection. Results iMacs displayed enhanced migration, faster phagocytosis and increased expression of autophagy‐ and apoptosis‐related proteins compared with MDMs. Moreover, iMacs showed a stronger pro‐inflammatory cytokine response and rapid return to baseline cytokine levels post‐infection. Conclusion These findings support the potential of iMacs as an immunocompetent model for studying mycobacterial infections and as a tool for cell‐based TB immunotherapies.