Neutrophil fate in bone infection: Mechanisms, microenvironment, and therapeutic opportunities

The clinical challenge of eradicating bone infection stems from microbial persistence within a distinct skeletal niche that is poorly perfused, hypoxic, mineralised, and highly susceptible to collateral damage. Neutrophils are central arbiters of this process and function as a double-edged sword: they are indispensable for initial pathogen containment, yet can become major drivers of chronic osteolysis, biofilm persistence, and inflammation when their effector programmes turn maladaptive. Recent high-resolution single-cell and spatial analyses have overturned the traditional view of neutrophils as short-lived, homogeneous cells, instead revealing a complex spectrum of functional states shaped by the infected bone microenvironment. In this Review, we use a neutrophil fate framework that distinguishes three related but non-equivalent levels: irreversible terminal fates, non-terminal tissue-disposition states and outcomes, and upstream fate-biasing states or processes. Terminal fates include apoptosis with subsequent efferocytic clearance, suicidal NETosis, pyroptosis, necroptosis, ferroptosis, mitochondrial permeability transition-driven necrosis, and secondary necrosis. By contrast, non-lytic (vital) NET release is considered an effector process rather than a terminal fate. Reverse migration is treated as a non-terminal tissue-exit outcome, whereas inflammatory retention is considered a non-terminal persistence state. Upstream fate-biasing factors include phenotypic or activation states, such as cellular ageing, NET-prone activation, and apoptosis delay, as well as regulatory processes including autophagy and metabolic or redox stress; none of these is classified as an independent terminal fate. We further examine how these terminal fates, non-terminal tissue-disposition states and outcomes, and upstream fate-biasing states and processes are spatially organised across osteomyelitic lesions and biofilm-associated interfaces, and how they govern interactions with osteoblasts, osteoclasts, and macrophages to determine the balance between antimicrobial control and progressive skeletal destruction. We also discuss emerging therapeutic paradigms aimed not at broadly suppressing neutrophil recruitment, but at precisely redirecting neutrophil fate, thereby providing a conceptual basis for stage-specific immunomodulation in orthopaedic infection. The Translational Potential of this Article This Review provides a fate-based framework for understanding how neutrophils shape the balance between pathogen control, biofilm persistence, osteolysis, and tissue repair in orthopaedic infection. By linking neutrophil fate programmes to distinct lesion microenvironments, including osteomyelitic lesions, implant-associated biofilms, contiguous soft-tissue infection, and fracture-related infection, this article highlights potential translational opportunities for stage- and compartment-specific immune modulation. These include improving patient stratification, guiding the timing of surgical source control and implant retention or removal, optimising dead-space management and local antimicrobial delivery, supporting vascularised soft-tissue reconstruction, and developing biomarkers that distinguish protective antimicrobial neutrophil responses from destructive inflammatory persistence. This framework may help shift future orthopaedic infection management from nonspecific suppression of inflammation toward precision redirection of maladaptive neutrophil fate while preserving early host defence and tissue repair capacity.