From acute infection to chronic osteoimmune remodeling: immunopathogenesis and precision immunotherapeutic strategies in osteomyelitis.

Osteomyelitis is a severe infectious and inflammatory disease that significantly affects bone tissue. It progresses from an acute inflammatory response to refractory chronic osteomyelitis and bone defects, constituting a core challenge in current clinical therapeutics and functional reconstruction. In the acute osteomyelitis stage, innate immune cells such as neutrophils, monocytes-macrophages, and dendritic cells are rapidly recruited and release large amounts of cytokines, chemokines, and extracellular traps. These work in synergy with adaptive immune responses, including T/B cells, to form the first line of defense for early pathogen clearance. However, when pathogens achieve immune escape through strategies such as biofilm formation, small colony variant (SCVs) phenotypes, and virulence factor reprogramming, and induce acquired immune tolerance and bone marrow-periosteal microenvironment remodeling, acute inflammation can evolve into persistent chronic osteomyelitis, accompanied by progressive bone destruction and recurrent relapses. Additionally, autoinflammatory bone diseases, represented by chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis (CNO/CRMO), also present an "osteomyelitis-like" immune profile characterized by abnormal activation of innate immunity and inflammatory pathways in the absence of clear infection. Accordingly, this review systematically reviews the key immunological mechanisms underlying the transition from acute to chronic osteomyelitis. It focuses on evaluating immunomodulatory and immunoengineering therapeutic strategies targeting the cytokine axis, immune checkpoints, and the bone-immune microenvironment, and discusses their clinical potential and practical challenges in personalized diagnosis and treatment. The aim is to provide a theoretical basis for a deeper understanding of the immunopathology of osteomyelitis and the development of innovative therapies. Special emphasis is placed on the differences in immune cell lineage composition, inflammatory mediator networks, and tissue microenvironment remodeling patterns between distinct etiologies of osteomyelitis (infectious osteomyelitis vs. autoinflammatory bone diseases), and their implications for precise phenotypic stratification and the selection of individualized immune intervention strategies.