The role of the microbial-immune-bone axis in bone tumor development: mechanistic integration, systems modeling, and...

The emergence and development of bone tumors stem from a combination of intrinsic genetic alterations in tumor cells, remodeling of the bone marrow microenvironment, and shifts in the host's systemic immune-metabolic state. In recent years, gut microorganisms have been shown not only to influence bone mass regulation and conditions involving disrupted bone homeostasis, such as osteoporosis, but also to substantially affect the formation of primary bone tumors and metastatic lesions by modulating immune cell differentiation, inflammatory activity, and the coupling of bone remodeling. Focusing on the "Microbiota-Immune-Bone axis" (MIB), a growing body of fundamental and translational research indicates that alterations in gut microbial composition and function can reshape metabolite profiles-including short-chain fatty acids, bile acids, indole derivatives-and pathogen-associated molecular patterns (PAMPs). These signals act on the intestinal barrier and bone marrow immunity through G-protein-coupled receptors, nuclear receptors, and pattern-recognition receptors, thereby shifting the balance between bone resorption and formation and modifying the immune characteristics of the bone microenvironment, ultimately facilitating bone tumor cell colonization, proliferation, and immune escape. This review takes the MIB axis as its central framework to integrate the major pathways through which gut microbes and their metabolites regulate intestinal and myeloid immunity, bone remodeling, and bone tumor biology, to construct a systems-level model of tumor initiation and progression, to identify druggable signaling nodes, and to assess the potential and challenges of microbiota-modulating approaches-including antibiotics, probiotics, dietary strategies, and fecal microbiota transplantation-in preventing and treating bone tumors, thereby offering a theoretical foundation for developing integrated interventions targeting the gut microbiota and the MIB axis.