Programmed cell death networks in tuberculosis: from molecular crosstalk to lesion immunopathology and host-directed therapy.

Mycobacterium tuberculosis (M. tuberculosis) has evolved to survive within host phagocytes while provoking inflammatory tissue destruction, a delicate balance that is critically shaped by programmed cell death (PCD). Rather than acting as isolated linear pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy/xenophagy, ETosis/NETosis, PARP1-AIF/parthanatos-related signaling, and PANoptosis-related signaling form an interconnected network that determines macrophage fate, granuloma integrity, bacterial dissemination, and immunopathology. In this Review, we discuss how M. tuberculosis and host-derived signals engage canonical cell-death modules, including caspases, RIPK1/RIPK3-MLKL, inflammasomes-gasdermins, ROS-iron-lipid peroxidation circuits, PARP1-AIF signaling, and autophagy machinery. We highlight context-dependent effects whereby apoptosis and autophagy may promote bacterial containment, whereas necrotic and inflammatory forms of death can either enhance antimicrobial immunity or drive caseation and tissue damage. We further evaluate emerging evidence for crosstalk among PCD modalities, with particular attention to shared molecular checkpoints and the still-evolving concept of PANoptosis in tuberculosis. Finally, we discuss host-directed therapeutic strategies aimed at recalibrating, rather than simply blocking or activating, cell-death pathways. A network-based understanding of PCD in M. tuberculosis infection provides a crucial framework for developing adjunctive therapies that enhance pathogen control while limiting destructive inflammation. Unlike pathway-centered summaries, this Review reframes M. tuberculosis-induced cell death as a dynamic network in which shared molecular hubs, compensatory switching, and lesion-stage-specific microenvironments jointly determine disease outcome.